The human internal environment is regulated in large measure by the integrated activity of the autonomic nervous system and endocrine glands. Their visceral and homeostatic functions, essential to life and survival, are involuntary. Why the forces of evolution favored this separation from volition is an interesting question. Claude Bernard expressed this idea in sardonic terms when he wrote, “nature thought it prudent to remove these important phenomena from the caprice of an ignorant will.”
Although only few neurologic diseases exert their effects primarily or exclusively on the autonomic–neuroendocrine axis, there are numerous medical diseases that implicate this system in some way: hypertension, asthma, and certain disorders of cardiac conduction including congestive heart failure, to name some of the important ones. However, many general neurologic diseases involve the autonomic nervous system to a varying extent, giving rise to symptoms such as orthostatic intolerance and syncope, sphincteric dysfunction, pupillary abnormalities, erectile dysfunction, diaphoresis, cardiac dysrhythmias, and disorders of thermoregulation. Finally, in addition to their central role in visceral innervation, autonomic parts of the neuraxis and parts of the endocrine system are engaged in all emotional experience and its display, as discussed in Chap. 24.
Breathing is unusual among nervous system functions. Although continuous throughout life, it is not altogether automatic, being partly under volitional control. Current views of the central and peripheral control of breathing, and the ways in which it is altered by certain diseases are of considerable interest to neurologists, if for no other reason than respiratory failure is common in neurologic conditions such as coma, cervical spinal cord injury, and a large number of acute and chronic neuromuscular diseases. Many of these same comments pertain to the function of swallowing, which is largely automatic and continues at regular intervals even in sleep but is also initiated voluntarily. Furthermore, swallowing fails in ways similar to breathing as a consequence of neurologic diseases.
The autonomic, endocrine, and respiratory systems, although closely related, give rise to disparate clinical syndromes. This chapter deals more strictly with the autonomic nervous system and the neural mechanisms of respiration and swallowing, and the next chapter, with the hypothalamus and neuroendocrine disorders. The following discussion of anatomy and physiology serves as an introduction to both chapters.
THE AUTONOMIC NERVOUS SYSTEM
The most remarkable feature of the autonomic nervous system is that a major part of it is located outside the brain and spinal cord, in proximity to the visceral structures that it innervates. This position alone seems to symbolize its relative independence from the cerebrospinal system. In distinction to the somatic neuromuscular system, where a single motor neuron bridges the gap between the central nervous system (CNS) and the effector organ, in the autonomic nervous system there are always two efferent neurons serving this function, one (preganglionic) arising from its nucleus in the brainstem or spinal cord and the other (postganglionic) arising from specialized nerve cells in peripheral ganglia. Figure 25-1 illustrates this fundamental anatomic feature. Preganglionic neurons are part of CNS, forming a central autonomic network, which consists of reciprocally connected structures located at the cortex, hypothalamus, brainstem, and spine. Postganglionic neurons are divided into sympathetic and parasympathetic.
Sympathetic outflow from the spinal cord and the course and distribution of sympathetic fibers. The preganglionic fibers are in blue; postganglionic fibers are red and purple. (From Pick.)
The autonomic nervous system, from an anatomic point of view, is divided into two parts: the craniosacral, or parasympathetic, and the thoracolumbar, or sympathetic (Figs. 25-2 and 25-3). Systems differ architecturally in that the ganglion in the sympathetic nervous system is located in a contiguous and interconnected, longitudinal chain (sympathetic chain) paravertebrally, whereas the parasympathetic ganglia are distributed in proximity to the structures they innervate. Moreover, the main neurotransmitter of the postganglionic connection to the end organ is norepinephrine in the case of the sympathetic nerves and acetylcholine for parasympathetic innervation. There are exceptions with regard to the sympathetic innervation of sweat glands (sudomotor), which are cholinergic. The neurotransmitter between the pre- and postneurons throughout the autonomic nervous system, sympathetic and parasympathetic, is acetylcholine as reiterated further on. These synapses between pre- and postganglionic cholinergic nerves are not blocked by atropine (nicotinic) whereas the postganglionic impulses are blocked by atropine (muscarinic).
The parasympathetic (craniosacral) division of the autonomic nervous system. Preganglionic fibers extend from nuclei of the brainstem and sacral segments of the spinal cord to peripheral ganglia. Short postganglionic fibers extend from the ganglia to the effector organs. The lateral-posterior hypothalamus is part of the supranuclear mechanism for the regulation of parasympathetic activities. The frontal and limbic parts of the supranuclear regulatory apparatus are not indicated in the diagram (see text). (Reproduced by permission from Noback CL, Demarest R: The Human Nervous System, 3rd ed. New York, McGraw-Hill, 1981.)
The sympathetic (thoracolumbar) division of the autonomic nervous system. Preganglionic fibers extend from the intermediolateral nucleus of the spinal cord to the peripheral autonomic ganglia, and postganglionic fibers extend from the peripheral ganglia to the effector organs, according to the scheme in Fig. 25-1. (Reproduced by permission from Noback CL, Demarest R: The Human Nervous System, 3rd ed. New York, McGraw-Hill, 1981.)
Functionally, the two parts are complementary in maintaining a balance in the tonic activities of many visceral structures and organs. This rigid separation into sympathetic and parasympathetic parts, although useful for purposes of exposition, is physiologically not absolute. From a neurologist’s perspective, the two components are often affected together. Nonetheless, the notion of a balanced sympathetic and parasympathetic autonomic system has stood the test of time and remains a valid concept.
The Parasympathetic Nervous System
There are two divisions of the parasympathetic nervous system: cranial and sacral (See Fig. 25-2). The cranial division originates in the visceral nuclei of the midbrain, pons, and medulla. These nuclei include the Edinger-Westphal pupillary nucleus, superior and inferior salivatory nuclei, dorsal motor nucleus of the vagus, and adjacent reticular nuclei.
Axons (preganglionic fibers) of the visceral cranial nuclei course through the oculomotor, facial, glossopharyngeal, and vagus cranial nerves. The preganglionic fibers from the Edinger-Westphal nucleus traverse the oculomotor nerve and synapse in the ciliary ganglion in the orbit; axons of the ciliary ganglion cells innervate the ciliary muscle and pupillary sphincter (see Fig. 13-9).
The preganglionic fibers of the superior salivatory nucleus enter the facial nerve and, at a point near the geniculate ganglion, form the greater superficial petrosal nerve, through which they reach the sphenopalatine ganglion; postganglionic fibers from the cells of this ganglion innervate the lacrimal gland (see also Figs. 25-2 and 44-3). Other fibers originating in the salivatory nuclei are carried in the facial nerve and traverse the tympanic cavity as the chorda tympani to eventually join the submandibular ganglion. Cells of this ganglion innervate the submandibular and sublingual glands. Axons of the inferior salivatory nerve cells enter the glossopharyngeal nerve and reach the otic ganglion through the tympanic plexus and lesser superficial petrosal nerve; cells of the otic ganglion send fibers to the parotid gland.
Preganglionic fibers, derived from the dorsal motor nucleus of the vagus and adjacent visceral nuclei in the lateral reticular formation (mainly the nucleus ambiguus), enter the vagus nerve and terminate in ganglia situated in the walls of many thoracic and abdominal viscera. The ganglionic cells give rise to short postganglionic fibers that activate smooth muscle and glands of the pharynx, esophagus, and gastrointestinal tract (the vagal innervation of the colon is somewhat uncertain but considered to extend up to the descending colon) and of the heart, pancreas, liver, gallbladder, kidneys, and ureter.
The sacral part of the parasympathetic system originates in the lateral horn cells of the second, third, and fourth sacral segments. Axons of these sacral neurons, constituting the preganglionic fibers, traverse the sacral spinal nerve roots of the cauda equina and synapse in ganglia that lie within the walls of the distal colon, bladder, and other pelvic organs. Thus, the sacral autonomic neurons, like the cranial ones, have long preganglionic and short postganglionic fibers, a feature that permits a circumscribed influence upon the target organ.
In organs containing smooth muscle that is innervated by parasympathetic fibers and therefore not under voluntary control, there is a parallel innervation of adjacent voluntary striated muscle by anterior horn cells. For example, the neurons that activate the external sphincter of the bladder (voluntary muscle) differ from those that supply the smooth muscle of the internal sphincter as discussed further on. In 1900, Onufrowicz (calling himself Onuf) described a discrete group of relatively small cells in the anterior horns of sacral segments 2 to 4. These neurons were originally thought to be autonomic in function, mainly because of their histologic features. There is now evidence that they are somatomotor, innervating the skeletal muscle of the external urethral and anal sphincters (Holstege and Tan). Neurons in sacral cord segments located in a region analogous to the intermediolateral cell column of the sympathetic nervous system (see later), innervate the detrusor and internal sphincter of the bladder wall. In passing, it is worth noting that in motor system disease, in which bladder and bowel functions are usually preserved until late in the disease, the neurons in the Onuf nucleus, in contrast to other somatomotor neurons in the sacral cord, tend not to be involved in the degenerative process (Mannen et al).
There are elaborate connections between supranuclear centers, mainly in the hypothalamus, to the pupillary sphincters, lacrimal and salivary glands that course the brainstem. With regard to the supranuclear innervation of parasympathetic nuclei in the sacral segments, little is known. There appear to be connections to these neurons from the hypothalamus, locus ceruleus, and pontine micturition centers but their course in the human spinal cord has not been identified with certainty.
The Sympathetic Nervous System
The preganglionic neurons of the sympathetic division originate in the intermediolateral cell column of the spinal gray matter, from the eighth cervical to the second lumbar segments (See Fig. 25-3). Low and Dyck (1977) have estimated that each segment of the cord contains approximately 5,000 lateral horn cells and that there is an attrition of 5 to 7 percent per decade in late adult life. The axons of the nerve fibers originating in the intermediolateral column are of small caliber and are myelinated; when grouped, they form the white communicating rami as shown in Fig. 25-1. These preganglionic fibers synapse with the cell bodies of the postganglionic neurons, which are collected into two large ganglionated chains or cords, one on each side of the vertebral column (paravertebral ganglia), and several single prevertebral ganglia. These constitute the sympathetic ganglia.
Axons of the sympathetic ganglion cells are also of small caliber but are unmyelinated. Most of the postganglionic fibers pass via gray communicating rami to their adjacent spinal nerves of T5 to L3; they supply blood vessels, sweat glands, and hair follicles, and also form plexuses that supply the heart, bronchi, kidneys, intestines, pancreas, bladder, and sex organs. The postganglionic fibers of the prevertebral ganglia (located in the retroperitoneal posterior abdomen rather than paravertebrally, along the sides of the spinal column) form the hypogastric, splanchnic, and mesenteric plexuses, which innervate the glands, smooth muscle, and blood vessels of the abdominal and pelvic viscera (see Fig. 25-3).
The sympathetic innervation of the adrenal medulla is unique in that its secretory cells receive preganglionic fibers directly, via the splanchnic nerves. This is an exception to the rule that organs innervated by the autonomic nervous system receive only postganglionic fibers. This special arrangement can be explained by the fact that cells of the adrenal medulla are the morphologic homologues of the postganglionic sympathetic neurons and secrete epinephrine and norepinephrine (the postganglionic transmitters) directly into the bloodstream. In this way, the sympathetic nervous system and the adrenal medulla act in unison to produce diffuse effects, as one would expect from their role in emergency reactions.
There are 3 cervical (superior, middle, and inferior, or stellate), 11 thoracic, and 4 to 6 lumbar sympathetic ganglia. The head receives its sympathetic innervation from the eighth cervical and first two thoracic cord segments, the fibers of which pass through the inferior to the middle and superior cervical ganglia. Postganglionic fibers from cells of the superior cervical ganglion follow the internal and external carotid arteries and innervate the blood vessels and smooth muscle, as well as the sweat, lacrimal, and salivary glands of the head. Included among these postganglionic fibers, issuing mainly from T1, are the pupillodilator fibers and those innervating the Müller muscle of the upper eyelid (it connects the upper tarsus to the undersurface of the levator); there is a separate small inferior tarsus muscle that is also sympathetically innervated. The arm receives its postganglionic innervation from the inferior cervical ganglion and uppermost thoracic ganglia (the two are fused to form the stellate ganglion). The cardiac plexus and other thoracic sympathetic nerves are derived from the stellate ganglion and the abdominal visceral plexuses, from the fifth to the ninth or tenth thoracic ganglia. The lowermost thoracic ganglia have no abdominal visceral connections; their axons course rostrally and caudally in the sympathetic chain. The upper lumbar ganglia supply the descending colon, pelvic organs, and legs.
The terminals of autonomic nerves and their junctions with smooth muscle and glands have been more difficult to visualize and study than the motor end plates of striated muscle. As the postganglionic axons enter an organ, usually via the vasculature, they ramify into many smaller branches and disperse, without a Schwann cell covering, to innervate the smooth muscle fibers, the glands, and, in largest number, the small arteries, arterioles, and precapillary sphincters (see Burnstock). Some of these terminals penetrate the smooth muscle of the arterioles; others remain in the adventitia. At the ends of the postganglionic fibers and in part along their course there are swellings that lie in close proximity to the sarcolemma or gland cell membrane; often the muscle fiber is grooved to accommodate these swellings. The axonal swellings contain synaptic vesicles, some clear and others with a dense granular core. The clear vesicles contain acetylcholine and those with a dense core contain catecholamines, particularly norepinephrine (Falck). This is well illustrated in the iris, where nerves to the dilator muscle (sympathetic) contain dense-core vesicles and those to the constrictor (parasympathetic) contain clear vesicles. A single nerve fiber innervates multiple smooth muscle and gland cells.
Somewhat arbitrarily, anatomists have declared the autonomic nervous system to be purely efferent motor and secretory in function. However, most autonomic nerves are mixed, also containing afferent fibers that convey sensory impulses from the viscera and blood vessels. The cell bodies of these sensory neurons lie in the posterior root sensory ganglia; some central axons of these ganglionic cells synapse with lateral horn cells of the spinal cord and subserve visceral reflexes; others synapse in the dorsal horn and convey or modulate impulses for conscious sensation. Secondary afferents carry sensory impulses to certain brainstem nuclei, particularly the nucleus tractus solitarius, as described later, and the thalamus via the lateral spinothalamic and polysynaptic pathways.
The Central Regulation of Visceral Function
The principal functions of central autonomic network are the modulation of stress responses, baroregulation, thermoregulation and energy balance. Integration of autonomic function takes place at two levels, the brainstem and the cerebrum. In the brainstem, the main visceral afferent nucleus is the nucleus tractus solitarius (NTS). Cardiovascular, respiratory, and gastrointestinal afferents, carried in cranial nerves X and IX via the nodose and petrosal ganglia, terminate on specific subnuclei of the NTS. The caudal subnuclei are the primary receiving site for viscerosensory fibers; other less-well-defined areas receive baroreceptor and chemoreceptor information. The caudal NTS integrates these signals and projects to a number of critical areas in the hypothalamus, amygdala, and insular cortex, involved primarily in cardiovascular control, as well as to the pontine and medullary nuclei controlling respiratory rhythms. The NTS therefore serves a critical integratory function for both circulation and respiration, as described further on.
Perhaps the major advance in our understanding of the autonomic nervous system occurred with the elaboration of the autonomic regulating functions of the hypothalamus. Small, insignificant-appearing nuclei in the walls of the third ventricle and in buried parts of the limbic cortex have rich bidirectional connections with autonomic centers in various parts of the nervous system. As indicated in Chap. 24, the hypothalamus serves as the integrating mechanism of the autonomic nervous system and limbic system. The regulatory activity of the hypothalamus is accomplished in two ways, through direct pathways that descend to particular groups of cells in the brainstem and spinal cord, and through the pituitary and thence to other endocrine glands. The supranuclear regulatory apparatus of the hypothalamus includes three main cerebral structures: the frontal lobe cortex, the insular cortex, and the amygdaloid and adjacent nuclei.
The ventromedial prefrontal and cingulate cortices function as the highest levels of autonomic integration. Stimulation of one frontal lobe may evoke changes in temperature and sweating in the contralateral arm and leg; massive lesions here, which usually cause a hemiplegia, may modify the autonomic functions in the direction of either inhibition or facilitation. Lesions involving the posterior part of the superior frontal and anterior part of the cingulate gyri (usually bilateral, occasionally unilateral) result in loss of voluntary control of the bladder and bowel. Most likely a large contingent of these fibers terminates in the hypothalamus, which, in turn, sends fibers to the brainstem and spinal cord. The descending spinal pathways from the hypothalamus are believed to lie ventromedial to the corticospinal fibers.
The insular cortex receives projections from the NTS, the parabrachial nucleus of the pons, and the lateral hypothalamic nuclei. Direct stimulation of the insula produces cardiac arrhythmias and a number of other alterations in visceral function. The cingulate and hippocampal gyri and their associated subcortical structures (substantia innominata and the amygdaloid, septal, piriform, habenular, and midbrain tegmental nuclei) have been identified as important cerebral autonomic regulatory centers. Together they have been called the visceral brain (see Chap. 24). Of particular importance in autonomic regulation is the amygdala, the central nucleus of which is a major site of origin of projections to the hypothalamus and brainstem. The anatomy and the effects of stimulation and ablation of the amygdala have been discussed in Chap. 24, in relation to the neurology of emotion.
In addition to the aforementioned central relationships, it should be noted that important interactions between the autonomic nervous system and the endocrine glands occur at a peripheral level. The best-known example is in the adrenal medulla. A similar relationship pertains to the pineal gland, in which norepinephrine (NE) released from postganglionic fibers that end on pineal cells stimulates several enzymes involved in the biosynthesis of melatonin. Similarly, the juxtaglomerular apparatus of the kidney and the islets of Langerhans of the pancreas may function as neuroendocrine transducers insofar as they convert a neural stimulus (in these cases adrenergic) to an endocrine secretion (renin, glucagon, and insulin, respectively). The numerous autonomic–endocrine interactions are elaborated in the next chapter.
Finally, there is the essential role that the hypothalamus plays in the initiation and regulation of autonomic activity, both sympathetic and parasympathetic. Sympathetic responses are most readily obtained by stimulation of the posterior and lateral regions of the hypothalamus, and parasympathetic responses from the anterior regions. The descending sympathetic fibers are largely or totally uncrossed. According to Carmel, fibers from the caudal hypothalamus at first run in the prerubral field, dorsal and slightly rostral to the red nucleus, and then ventral to the ventrolateral thalamic nuclei; then they descend in the lateral tegmentum of the midbrain, pons, and medulla to synapse in the intermediolateral cell column of the spinal cord. In the medulla, the descending sympathetic pathway is located in the posterolateral retroolivary area, where it is frequently involved in lateral medullary infarctions. In the cervical cord, the fibers run in the posterior angle of the anterior horn (Nathan and Smith). According to the latter authors, some of the fibers supplying sudomotor neurons run outside this area but also remain ipsilateral. Jansen and colleagues, by the use of viral vectors in rodents, were able to label certain neurons of the hypothalamus and the ventral medulla that stimulated sympathetic activity in both the stellate ganglion and the adrenal gland. They hypothesized that this dual control underlies the fight-or-flight response, as described in Chap. 24. By contrast, the pathways of descending parasympathetic fibers are not well defined.
Afferent projections from the spinal cord to the hypothalamus have been demonstrated in animals and provide a potential route by which sensation from somatic and possibly visceral structures may influence autonomic responses.
Physiologic and Pharmacologic Considerations
The function of the autonomic nervous system in its regulation of the visceral organs is to a high degree independent of voluntary control and awareness. Furthermore, when the autonomic nerves are interrupted, these organs continue to function (the organism survives), but they are no longer as effective in maintaining homeostasis and adapting to the demands of changing internal conditions and external stresses.
Viscera have a double-nerve supply, sympathetic and parasympathetic and in general these two parts of the autonomic nervous system exert opposite effects. For example, the effects of the sympathetic nervous system on the heart are excitatory and those of the parasympathetic inhibitory. However, some structures—sweat glands, cutaneous blood vessels, and hair follicles—receive only sympathetic postganglionic fibers, and the adrenal gland, as indicated earlier, has only a preganglionic sympathetic innervation. Also, some parasympathetic neurons have been identified in sympathetic ganglia.
All autonomic functions are mediated through the release of chemical transmitters. The modern concept of neurohumoral transmission had its beginnings in the early decades of the twentieth century. In 1921, Loewi discovered that stimulation of the vagus nerve released a chemical substance (Vagusstoff) that slowed the heart. Later this substance was shown by Dale to be acetylcholine (ACh). Also, in 1920, Cannon reported that stimulation of the sympathetic trunk released an epinephrine-like substance, which increased the heart rate and blood pressure. He named this substance “sympathin,” subsequently shown to be norepinephrine, or NE. Dale found that ACh had pharmacologic effects similar to those obtained by stimulation of parasympathetic nerves; he designated these effects as “parasympathomimetic.” These observations placed neurochemical transmission on solid ground and laid the basis for the distinction between cholinergic and adrenergic transmission in the autonomic nervous system.
The most important of the autonomic neurotransmitters are ACh and NE. ACh is synthesized at the terminals of axons and stored in presynaptic vesicles until it is released by the arrival of nerve impulses. ACh is released at the terminals of all preganglionic fibers (in both the sympathetic and parasympathetic ganglia), as well as at the terminals of all postganglionic parasympathetic and a few special postganglionic sympathetic fibers, mainly those subserving sweat glands. Of course, ACh is also the chemical transmitter of nerve impulses to the skeletal muscle fibers. Parasympathetic postganglionic function is mediated by two distinct types of ACh receptors: nicotinic and muscarinic, so named by Dale because the choline-induced responses were similar either to those of nicotine or to those of the alkaloid, muscarine. The postganglionic parasympathetic receptors are located within the innervated organ and are muscarinic; that is, they are antagonized by atropinic drugs. As already mentioned the receptors in ganglia, like those of skeletal muscle, are nicotinic; they are not blocked by atropine but are counteracted by other agents (e.g., tubocurarine).
It is likely that more than ACh is involved in nerve transmission at a ganglionic level. Many peptides—substance P, enkephalins, somatostatin, vasoactive intestinal peptide, adenosine triphosphate (ATP), and nitric oxide—have been identified in the autonomic ganglia, localizing in some cases to the same cell as ACh. (This negates “Dale’s principle,” or “law,” which stipulates that one neuron elaborates only one neurotransmitter, as outlined by Tansey.) Particular neuronal firing rates appear to cause the preferential release of one or another of these substances. Most of the neuropeptides exert their postsynaptic effects through the G-protein transduction system, which uses adenyl cyclase or phospholipase C as an intermediary. The neuropeptides act as modulators of neural transmission, although their exact function in many cases remains to be determined.
With two exceptions, postganglionic sympathetic fibers release only NE at their terminals. The sweat glands and some blood vessels in muscle are innervated by postganglionic sympathetic fibers, but their terminals, as mentioned, release ACh. The NE that is discharged into the synaptic space activates specific adrenergic receptors on the postsynaptic membrane of target cells.
Adrenergic receptors are of two types, classified originally by Ahlquist as alpha and beta. In general, the alpha receptors mediate vasoconstriction, relaxation of the gut, and dilatation of the pupil; beta receptors mediate vasodilatation, especially in muscles, relaxation of the bronchi, and an increased rate and contractility of the heart. Each of these receptors is subdivided further into two types. Alpha1 receptors are postsynaptic; alpha2 receptors are situated on the presynaptic membrane and, when stimulated, diminish the release of the transmitter. Beta1 receptors are, for all practical purposes, limited to the heart; their activation increases the heart rate and contractility. Beta2 receptors, when stimulated, relax the smooth muscle of the bronchi and of most other sites, including the blood vessels of skeletal muscle. A comprehensive account of neurohumoral transmission and receptor function can be found in the monograph by Cooper and colleagues.
Discussed in the following pages are the ways in which the two divisions of the autonomic nervous system, acting in conjunction with the endocrine glands, maintain the homeostasis of the organism. As stated earlier, the integration of these two systems is achieved primarily in the hypothalamus. In addition, the endocrine glands are influenced by circulating catecholamines, and some of them are innervated by adrenergic fibers. Chapter 26 discusses further these autonomic–endocrine relations.
Regulation of Blood Pressure
As was indicated briefly in Chap. 17, blood pressure depends on the adequacy of intravascular blood volume, on systemic vascular resistance, and on the cardiac output. Both the autonomic and endocrine systems influence the muscular, cutaneous, and mesenteric (splanchnic) vascular beds, heart rate, and stroke volume of the heart. Together, these actions serve to maintain normal blood pressure and allow reflex maintenance of blood pressure with changes in body position. Two types of baroreceptors function as the afferent component of this reflex arc by sensing pressure gradients across the walls of large blood vessels. Those in the carotid sinus and aortic arch are sensitive to reductions in pulse pressure (the difference between systolic and diastolic blood pressure), while those in the right heart chambers and pulmonary vessels respond more to alterations in blood volume. The carotid sinus baroreceptors are rapidly responsive and capable of detecting beat-to-beat changes, in contrast to the aortic arch nerves, which have a longer response time and discriminate only the larger and more prolonged alterations in pressure.
The nerves arising from these receptors are small-caliber, thinly myelinated fibers that course in cranial nerves IX and X and terminate in the nucleus of the tractus solitarius (NTS). In response to increased stimulation of these receptors, vagal efferent activity is reduced, resulting in reflex cardioacceleration. This is accomplished through polysynaptic connections between the NTS and the dorsal motor nucleus of the vagus; it is from this structure that vagal neurons project to the sinoatrial node, atrioventricular node, and the muscle of the left ventricle. Thus, vagal activity results in reduction in heart rate and in the contractile force of the myocardium (negative inotropy). Increased systemic vascular resistance is mediated concurrently through parallel connections between the NTS and the medullary pressor areas that project to the intermediolateral cells of the midthoracic cord. The main sympathetic outflow from these thoracic segments is via the greater splanchnic nerve to the celiac ganglion, the postganglionic nerves of which project to the capacitance vessels of the gut. The splanchnic capacitance veins act as a reservoir for as much as 20 percent of the total blood volume, and interruption of the splanchnic nerves results in severe postural hypotension. After a high-carbohydrate meal there is a marked hyperemia of the gut and compensatory peripheral vasoconstriction in the muscles and skin. It has also been noted that the mesenteric vascular bed is responsive to the orthostatic redistribution of blood volume but not to mental stress.
The opposite response to the one described earlier, namely bradycardia and hypotension, results when vagal tone is enhanced and sympathetic tone reduced. This response can be triggered by baroreceptors, or it may arise from cerebral stimuli such as fear or sight of blood in susceptible individuals as well as from extreme pain, particularly arising in the viscera.
Two slower-acting humoral mechanisms regulate blood volume and complement the control of systemic vascular resistance. Pressure-sensitive renal juxtaglomerular cells release renin, which stimulates production of angiotensin and influences aldosterone production, both of which affect an increase of blood volume. Of lesser influence in the control of blood pressure is antidiuretic hormone, discussed in the next chapter; but the effects of this peptide become more important when autonomic failure forces a dependence on secondary mechanisms for the maintenance of blood pressure. In addition to its presence in autonomic ganglia, nitric oxide has been found to have an important local role in maintaining vascular tone, mainly by way of attenuating the response to sympathetic stimulation. The extent to which this latter function is under neural control is not clear.
Regulation of Bladder Function
The familiar functions of the bladder and lower urinary tract—the storage and intermittent evacuation of urine—are served by three structural components: the bladder itself, the main component of which is the large detrusor (transitional type) muscle; a functional internal sphincter composed of similar muscle; and the striated external sphincter or urogenital diaphragm. The sphincters ensure continence; in the male, the internal sphincter also prevents the reflux of semen from the urethra during ejaculation. For micturition to occur, the sphincters must relax, allowing the detrusor to expel urine from the bladder into the urethra. This is accomplished by a complex mechanism involving mainly the parasympathetic nervous system (the sacral peripheral nerves derived from the second, third, and fourth sacral segments of the spinal cord and their somatic sensorimotor fibers) and, to a lesser extent, sympathetic fibers derived from the thorax. The vaguely localizable brainstem “micturition centers,” with their spinal and suprasegmental connections, may contribute (Fig. 25-4).
Innervation of the urinary bladder and its sphincters.
The detrusor muscle receives motor innervation from nerve cells in the intermediolateral columns of gray matter, mainly from the third and also from the second and fourth sacral segments of the spinal cord (the “detrusor center”). These neurons give rise to preganglionic fibers that synapse in parasympathetic ganglia within the bladder wall. Short postganglionic fibers end on muscarinic acetylcholine receptors of the muscle fibers. There are also beta-adrenergic receptors in the dome of the bladder, which are activated by sympathetic fibers that arise in the intermediolateral nerve cells of T10, T11, and T12 segments. These preganglionic fibers pass via inferior splanchnic nerves to the inferior mesenteric ganglia (see Fig. 25-1); pre- and postganglionic sympathetic axons are conveyed by the hypogastric nerve to the pelvic plexus and the bladder dome. The internal sphincter and base of the bladder (trigone), consisting of smooth muscle, are also innervated to some extent by the sympathetic fibers of the hypogastric nerves; their receptors are mainly of alpha-adrenergic type, which makes it possible to therapeutically manipulate the function of the sphincter with adrenergically active drugs as well as the more commonly used cholinergic ones (see further on).
The external urethral and anal sphincters are composed of striated muscle fibers. Their innervation, via the pudendal nerves, is derived from a densely packed group of somatomotor neurons (nucleus of Onuf) in the anterolateral horns of sacral segments 2, 3, and 4. Cells in the ventrolateral part of Onuf’s nucleus innervate the external urethral sphincter, and cells of the mediodorsal part innervate the anal sphincter. The muscle fibers of the sphincters respond to the nicotinic effects of ACh.
The pudendal nerves also contain afferent fibers coursing from the urethra and the external sphincter to the sacral segments of the spinal cord. These fibers convey impulses for reflex activities and, through connections with higher centers, for sensation. Some of these fibers probably course through the hypogastric plexus, as indicated by the fact that patients with complete transverse lesions of the cord as high as T12 may report vague sensations of urethral discomfort. The bladder is sensitive to pain and pressure; these senses are transmitted to higher centers along the sensory pathways described in Chaps. 7 and 8.
Unlike skeletal striated muscle, the detrusor, because of its postganglionic system, is capable of some contractions, although imperfect, after complete destruction of the sacral segments of the spinal cord. Isolation of the sacral cord centers (transverse lesions of the cord above the sacral levels) and their peripheral nerves permits contractions of the detrusor muscle, but they still do not empty the bladder completely; patients with such lesions usually develop dyssynergia of the detrusor and external sphincter muscles (see later), indicating that coordination of these muscles must occur at supraspinal levels (Blaivas). With acute transverse lesions of the upper cord, the function of sacral segments is abolished for several weeks in the same way as the motor neurons of skeletal muscles (the state of spinal shock).
The storage of urine and the efficient emptying of the bladder are possible only when the spinal segments, together with their afferent and efferent nerve fibers, are connected with the so-called micturition centers in the pontomesencephalic tegmentum. In experimental animals, this center (or centers) lies within or adjacent to the locus ceruleus. A medial region triggers micturition, while a lateral area seems more important for continence. These neurons receive afferent impulses from the sacral cord segments; their efferent fibers course downward via the reticulospinal tracts in the lateral funiculi of the spinal cord and activate cells in the nucleus of Onuf, as well as in the intermediolateral cell groups of the sacral segments (Holstege and Tan). In cats, the pontomesencephalic centers receive descending fibers from anteromedial parts of the frontal cortex, thalamus, hypothalamus, and cerebellum, but the brainstem centers and their descending pathways have not been precisely defined in humans. Other fibers from the motor cortex descend with the corticospinal fibers to the anterior horn cells of the sacral cord and innervate the external sphincter. According to Ruch, the descending pathways from the midbrain tegmentum are inhibitory and those from the pontine tegmentum and posterior hypothalamus are facilitatory. The pathway that descends with the corticospinal tract from the motor cortex is inhibitory. Thus the net effect of lesions in the brain and spinal cord on the micturition reflex, at least in animals, may be either inhibitory or facilitatory (DeGroat).
Almost all of this information has been inferred from animal experiments; there is little human pathologic material to corroborate the role of brainstem nuclei and cortex in bladder control. What information is available is reviewed extensively by Fowler, whose article is recommended. Also of interest here is the study by Blok and colleagues, who performed positron emission tomography (PET) studies in volunteer subjects during micturition. Increased blood flow was detected in the right pontine tegmentum, periaqueductal region, hypothalamus, and right inferior frontal cortex. When the bladder was full but subjects were prevented from voiding, increased activity was seen in the right ventral pontine tegmentum. The meaning of these lateralized findings is unclear, but the study supports the presumption that pontine centers are involved in the act of voiding.
The act of micturition is both reflex and voluntary. When the normal person desires to void, there is first a voluntary relaxation of the perineum, followed sequentially by an increased tension of the abdominal wall, a slow contraction of the detrusor, and an associated opening of the internal sphincter; finally, there is a relaxation of the external sphincter (Denny-Brown and Robertson). It is useful to think of the detrusor contraction as a spinal stretch reflex, subject to facilitation and inhibition from higher centers. Voluntary closure of the external sphincter and contraction of the perineal muscles cause the detrusor contraction to subside. The abdominal muscles have little role in initiating micturition except when the detrusor muscle is not functioning normally. The voluntary restraint of micturition is a cerebral affair and is mediated by fibers that arise in the frontal lobes (paracentral motor region), descend in the spinal cord just anterior and medial to the corticospinal tracts, and terminate on the cells of the anterior horns and intermediolateral cell columns of the sacral segments, as described earlier. The coordination of detrusor and external sphincteric function depends mainly on the descending pathway from the posited centers in the dorsolateral pontine tegmentum.
Regulation of Bowel Function
The colon and anal sphincters are obedient to the same principles that govern bladder function. Unique to the bowel, however, is an intrinsic enteric nervous system that originates in the myenteric (or Auerbach) plexus and the submucosal plexus (of Meissner), located in the gut wall. The first stimulates smooth muscle and the latter also regulates mucosal secretion and blood flow. This embedded system controls peristalsis largely independent of other autonomic influences but is highly responsive to local chemical and mechanical stimuli. As outlined in the thorough review by Benarroch that should be consulted by interested readers, acetylcholine is the dominant neurotransmitter in the enteric nerves but nitric oxide and numerous peptide transmitters are found in profusion.
Emergency and Alarm Reactions
The autonomic nervous system and the adrenal glands were accepted for many years as the neural and humoral basis of all instinctive and emotional behavior. In states of chronic anxiety and acute panic reactions, depressive psychosis, mania, and schizophrenia, all of which are characterized by an altered emotionality, no consistent autonomic or endocrine dysfunction has been demonstrated except perhaps for diminished responses of growth hormone in panic disorders. The lack of cortisol suppressibilty by injection of adrenocorticotropic hormone (ACTH) had for some time also been considered to be a consistent aspect of depressive illnesses but that too, has not been entirely specific. This has been disappointing, as the emergency theory of sympathoadrenal action provided by Cannon was such a promising concept of the neurophysiology of acute emotion, and Selye had extended this theory so plausibly to explain all the reactions to stress in animals and humans.
According to these theories, strong emotion, such as anger or fear, excites the sympathetic nervous system and the adrenal cortex (via corticotropin-releasing factor [CRF] and ACTH), which are under direct neural and endocrine control. These sympathoadrenal reactions are brief and sustain the animal in “flight or fight” as discussed in Chap. 24. Animals deprived of adrenal cortex or human beings with Addison disease cannot tolerate stress because they are incapable of mobilizing both the adrenal medulla and adrenal cortex. Prolonged stress and production of ACTH activates all the adrenal hormones (glucocorticoids, mineralocorticoids, and adrenocorticoids) and has been studied extensively in relation to immune reactions and other systemic functions but with no consistent findings that are yet clinically applicable.
Tests for Abnormalities of the Autonomic Nervous System
With few exceptions, such as testing pupillary reactions and examination of the skin for abnormalities of color and sweating, the neurologist tends to be casual in evaluating the function of the autonomic nervous system. Nonetheless, several simple but informative tests can be used to confirm one’s clinical impressions and to elicit abnormalities of autonomic function that may aid in diagnosis. For the detection of certain disease, it is almost imperative that blood pressure be evaluated to detect a drop with change in body position from lying or sitting, to standing. A combination of tests is usually necessary, because certain ones are particularly sensitive to abnormalities of sympathetic function and others to parasympathetic or baroreceptor afferent function. These are described later and are summarized in Table 25-1. A scheme for the examination of pupillary abnormalities was presented in Fig. 13-11.
Table 25-1CLINICAL TESTS OF AUTONOMIC FUNCTION ||Download (.pdf) Table 25-1CLINICAL TESTS OF AUTONOMIC FUNCTION
|TEST ||NORMAL RESPONSE ||MAIN PART OF REFLEX ARC TESTED |
|Noninvasive bedside tests || || |
| Blood-pressure response to standing or vertical tilt ||Fall in BP ≤30/15 mm Hg ||Afferent and sympathetic efferent limbs |
| Heart rate response to standing ||Increase 11–90 beats/min; 30:15 ratio ≥1.04 ||Vagal afferent and efferent limbs |
| Isometric exercise ||Increase in diastolic BP, 15 mm Hg ||Sympathetic efferent limb |
| Heart rate variation with respiration ||Maximum-minimum heart rate ≥15 beats/min; E:I ratio 1.2a ||Vagal afferent and efferent limbs |
| Valsalva ratio (see text) ||≥1.4a ||Afferent and efferent limbs |
| Sweat tests ||Sweating over all body and limbs ||Sympathetic efferent limb |
| Axon reflex ||Local piloerection, sweating ||Postganglionic sympathetic efferent fibers |
| Plasma noradrenaline level ||Rises on tilting from horizontal to vertical ||Sympathetic efferent limb |
| Plasma vasopressin level ||Rise with induced hypotension ||Afferent limb |
|Invasive tests || || |
| Valsalva maneuver (BP response with indwelling arterial catheter or continuous noninvasive BP measurement) || |
Phase I: Rise in BP
Phase II: Gradual reduction of BP to plateau; tachycardia
|Afferent and sympathetic efferent limbs |
| ||Phase III: Fall in BP || |
| ||Phase IV: Overshoot of BP, bradycardiaa || |
| Baroreflex sensitivity ||(1) Slowing of heart rate with induced rise of BPa ||(1) Parasympathetic afferent and efferent limbs |
| ||(2) Steady-state responses to induced rise and fall of BP ||(2) Afferent and efferent limbs |
| Infusion of pressor drugs ||(1) Rise in BP ||(1) Adrenergic receptors |
| ||(2) Slowing of heart rate ||(2) Afferent and efferent parasympathetic limbs |
|Other tests of vasomotor control || || |
| Radiant heating of trunk ||Increased hand blood flow ||Sympathetic efferent limb |
| Immersion of hand in hot water ||Increased blood flow of opposite hand ||Sympathetic efferent limb |
| Cold pressor test ||Reduced blood flow, rise in BP ||Sympathetic efferent limb |
| Emotional stress ||Increased BP ||Sympathetic efferent limb |
|Tests of pupillary innervation || || |
| 4% cocaine ||Pupil dilates ||Sympathetic innervation |
| 0.1% adrenaline ||No response ||Postganglionic sympathetic innervation |
| 1% hydroxyamphetamine hydrobromide ||Pupil dilates ||Postganglionic sympathetic innervation |
| 2.5% methacholine 0.125% pilocarpine ||No response ||Parasympathetic innervation |
| 0.5% apraclonidine ||Pupil dilates and ptosis resolves in Horner syndrome ||Parasympathetic innervation |
Testing of Blood Pressure and Heart Rate
These are among the simplest and most important tests of autonomic function and most laboratories have automated techniques to quantitate them. McLeod and Tuck state that in changing from the recumbent to the standing position, a fall of more than 30 mm Hg systolic and 15 mm Hg diastolic is abnormal; others give figures of 20 and 10 mm Hg. They caution that the arm on which the cuff is placed must be held horizontally when standing, so that the decline in arm pressure will not be obscured by the added hydrostatic pressure. As emphasized in Chap. 17 on syncope, the determination of blood pressure in orthostatic testing is ideally done by having the patient remain supine for as long as it is practical before testing, and shifting from a supine to standing position, without the interposition of sitting. Moreover, blood pressure is most informative if measured immediately after standing and again at approximately 1 and 3 min. The expected response is a momentary and slight increase in pressure that is usually not detected with a manual blood pressure cuff, followed by a slight drop within seconds of standing, and then a slow recovery during the first minute. Persistent hypotension at 1 min indicates sympathetic adrenergic failure and the later measurement affirms this if blood pressure fails to recover or continues to decline (Fig. 25-5).
Comparisons of normal responses to the tilt (Control) with orthostatic hypotension (OH). Normal heart rate (HR) increment (>10 BPM and < 30 BPM) is seen in both examples. Blood pressure is stable in a healthy control subject. The right panel shows supine hypertension and marked OH during the tilt. Cerebral blood flow velocity (CBFv) is stable in a control subject and reduced in OH. (Modified and with permission from Novak P: Cerebral blood flow, heart rate, and blood pressure patterns during the tilt test in common orthostatic syndromes. Neurosci J 2016:6127340, 2016 (epub).)
The main cause of an orthostatic drop in blood pressure is, of course, hypovolemia. In the context of recurrent fainting, however, an excessive drop reflects inadequate sympathetic vasoconstrictor activity. The use of a tilt table, as described in “Tilt-Table Testing” in Chap. 17 and further on, is an additional means of inducing orthostatic changes and also elicits reflex fainting in patients prone to syncope from an oversensitive cardiac reflex, that is, one that produces vasodilatation (neurocardiogenic syncope). In response to the induced drop in blood pressure, the heart rate (mainly under vagal control) normally increases. The failure of the heart rate to rise in response to the drop in blood pressure with standing is the simplest bedside indicator of vagal nerve dysfunction. Neurally mediated syncope may show one of three initial patterns with testing on a tilt table: a vasodepressor response alone (vasodepressor syncope), a combined bradycardic and hypotensive response (mixed syncope), and solely bradycardia (cardiovagal syncope) (Fig. 25-6). The mixed syncope is the most common form of neurally mediated syncope. The tilt table allows differentiation among these or, more often, clarifies the order in which the events occur.
Comparisons of three main types of neurally mediated syncope. Syncope is associated with profound decline in blood pressure and in diastolic cerebral blood flow velocity (CBFv). The heart rate and blood pressure responses differentiate each type of syncope while CBFv responses are similar among all syncope types. Heart rate declines before blood pressure in cardiovagal syncope, the heart rate decline is absent in the vasodepressor syncope and heart rate and blood pressure decline simultaneously in mixed syncope. CBFv shows typical vasodilation pattern in all types of syncope that is characterized by decline in diastolic and increase in systolic CBFv. The diastolic CBFv is equal or close to zero during syncope. (Modified and with permission from Novak P: Cerebral blood flow, heart rate, and blood pressure patterns during the tilt test in common orthostatic syndromes. Neurosci J 2016:6127340, 2016 (epub).)
In addition, the heart rate, after rising initially in response to upright standing posture (not with the tilt table), slows after about 15 beats to reach a stable rate by the thirtieth beat. The ratio of R-R intervals in the electrocardiogram (ECG), corresponding to the 30th and 15th beats (the 30:15 ratio), is an even more sensitive measure of the integrity of vagal inhibition of the sinus node. A ratio in adults under age 60 of less than 1.07 is usually abnormal, indicating a loss of vagal tone and the normal ratio is progressively higher for younger ages, for example, it is usually above 1.12 at age 30 and 1.1 at age 40.
Another simple procedure for quantitating purely vagal function consists of measuring the variation in heart rate during deep breathing (respiratory sinus arrhythmia). The ECG is recorded while the patient breathes at a regular rate of 6 breaths per minute. Normally, the heart rate varies by as many as 10 beats per minute or even more between expiration and inspiration; differences of less than 7 beats per minute for ages 60 to 69 and 9 for ages 50 to 59 may be abnormal.
A yet more accurate test of vagal function is the measurement of the ratio of the longest R-R interval during forceful slow expiration (standardized as constant blowing at a pressure of 40 mm Hg for 10 s) to the shortest R-R interval during inspiration, which allows the derivation of an expiration–inspiration (E:I) ratio. This is the best validated of all the heart-rate measurements, particularly as computerized methods can be used to display the spectrum of beat-to-beat ECG intervals during breathing. The results of these tests must always be compared with those obtained in normal individuals of the same age. Up to age 40 years, E:I ratios of less than 1.2 (signifying a variation of 20 percent) are abnormal. The ratio decreases with age, and markedly so beyond age 60 years (at which time it approaches 1.04 or less), as it does also in the presence of even mild diabetic neuropathy. Thus the test results must be interpreted cautiously in the elderly or in diabetic individuals. Similar ratios have been developed for heart-rate change during the Valsalva maneuver; the Valsalva ratio.
Computerized methods of power spectral analysis may be used to express the variance in heart rate as a function of the beat-to-beat interval. Several power peaks are appreciated: one related to the respiratory sinus arrhythmia and others that reflect baroreceptor and cardiac sympathetic activity. All of these tests of heart-rate variation are usually combined with measurement of heart rate and blood pressure during the Valsalva maneuver, as described below, and with the tilt-table test, as described in Chap. 17.
In the Valsalva maneuver, the subject exhales into a manometer or against a closed glottis for 10 s, creating a markedly positive intrathoracic pressure. The sharp reduction in venous return to the heart causes a drop in cardiac output and in blood pressure; the response on baroreceptors is to cause a reflex tachycardia and, to a lesser extent, peripheral vasoconstriction. With release of intrathoracic pressure, the venous return, stroke volume, and blood pressure rise to higher-than-normal levels; reflex parasympathetic influence then predominates and a bradycardia results (see Fig. 25-5). Failure of the heart rate to increase during the positive intrathoracic pressure phase of the Valsalva maneuver points to sympathetic dysfunction, and failure of the rate to slow during the period of blood pressure overshoot points to a parasympathetic disturbance. In patients with autonomic failure, the fall in blood pressure is not aborted during the last few seconds of increased intrathoracic pressure, and there is no overshoot of blood pressure when the breath is released. The Valsalva ratio, referring to the maximum heart rate generated by the maneuver to the lowest heart rate within 30 s of that peak, is another often-used measure in comprehensive autonomic testing.
Tests of Vasomotor Reactions
These generally test sympathetic cholinergic function. Measurement of the skin temperature is a rough but useful index of vasomotor function. Vasomotor paralysis results in vasodilatation of skin vessels and a rise in skin temperature; vasoconstriction lowers the temperature. With a skin thermometer, one may compare affected and normal areas under standard conditions. The normal skin temperature is 31°C (87.8°F) to 33°C (91.4°F) when the room temperature is 26°C (78.8°F) to 27°C (80.6°F). Vasoconstrictor tone may also be tested by measuring the reduction in skin temperature at a distant site before and after immersing one or both hands in cold water (see the discussion of the cold pressor test later).
The integrity of the sympathetic reflex arc, which includes baroreceptors in the aorta and carotid sinus, their afferent pathways, the vasomotor centers, and the sympathetic and parasympathetic outflow can be tested in a general way by combining the cold pressor test, grip test, mental arithmetic test, and Valsalva maneuver, as described below.
Vasoconstriction induces an elevation of the blood pressure. This is the basis of the cold pressor test. In normal persons, immersing one hand in ice water for 1 to 5 min raises the systolic pressure by 15 to 20 mm Hg and the diastolic pressure by 10 to 15 mm Hg. Similarly, the sustained isometric contraction of a group of muscles (e.g., those of the forearm in handgrip) for 5 min normally increases the heart rate and the systolic and diastolic pressures by at least 15 mm Hg. The response in both of these tests is reduced or absent with lesions of the sympathetic reflex arc, particularly of the efferent limb, but neither of these tests has been well quantitated or validated. The stress involved in doing mental arithmetic in noisy and distracting surroundings will also stimulate a mild but measurable increase in pulse rate and blood pressure. Obviously this response does not depend on the afferent limb of the sympathetic reflex arc and must be mediated by cortical–hypothalamic mechanisms.
If the response to the Valsalva maneuver is abnormal and the response to the cold pressor test is normal, the lesion is probably in the baroreceptors or their afferent nerves; such a defect has been found in diabetic and tabetic patients and is common in many neuropathies. A failure of the heart rate and blood pressure to rise during mental arithmetic coupled with an abnormal Valsalva maneuver suggests a defect in the central or peripheral efferent sympathetic pathways.
Tests of Sudomotor Function
The integrity of sympathetic efferent pathways can be assessed further by tests of sudomotor activity. There are several of these, all used mainly in specialized autonomic testing laboratories. The most rudimentary tests involve weighing sweat after it is absorbed by small squares of filter paper. Also, powdered charcoal dusted on the skin will cling to moist areas and not to dry ones. The starch iodine (Minor) is a qualitative test, which uses color changes of cornstarch dusted on the skin covered with tincture iodine. Minor’s tests can be used to detect hypo- or hyperhidrosis. Previously described quinizarin (gray when dry, purple when wet) uses similar principle. The methods described above reflect postganglionic sudomotor function.
In the sympathetic or galvanic skin-resistance test, a set of electrodes placed on the skin measures the resistance to the passage of a weak current through the skin; in all likelihood, the change in electrical potential is the result of an ionic current within the sweat glands, not simply an increase in sweating that lowers skin resistance. This method can be used to outline an area of reduced sweating because of a peripheral nerve lesion, as the response depends on sympathetic activation of sweat glands (Gutrecht). However, the galvanic skin response is subject to habituation with repeated stimuli and will show no response if there is a sensory neuropathy. The silicone imprint method is a quantitative postganglionic test that measures sweat droplets induced by iontophoresis of acetylcholine, pilocarpine, or methacholine. Although in theory quantitative, the imprint methods are prone to artefacts (see Stewart et al).
A more quantitative and reproducible examination of postganglionic sudomotor function, termed QSART (quantitative sudomotor axon reflex test), has been developed and studied extensively by Low. It is essentially a test of distal sympathetic axonal integrity utilizing the local axon reflex. A 10 percent solution of acetylcholine is iontophoresed onto the skin using 2 mA for 5 min. Sweat output is recorded in the adjacent skin by sophisticated circular cells that detect the sweat water. The forearm, proximal leg, distal leg, and foot have been chosen as standardized recording sites. By this test, Low has been able to define patterns of absent or delayed sweating that signify postganglionic sympathetic failure in small-fiber neuropathies and excessive sweating or reduced latency in response, as is seen in reflex sympathetic dystrophy. This is the preferred method of studying sweating and the function of distal sympathetic fibers, but its technical complexity makes it available only in specially equipped laboratories.
The thermoregulatory sweat testing (TST) measures the integrity of the central and peripheral sympathetic sudomotor pathways. The test is conducted by raising the core body temperature by increasing the ambient temperature and the sweating pattern is visualized with an indicator dye. This may show striking results but is time consuming, needs special patient preparation, and large clinical space. The advantage of TST is that in combination with tests measuring postganglionic functions, it can differentiate between postganglionic (all tests abnormal) versus preganglionic (only TST abnormal) failure.
Tearing can be estimated roughly by inserting one end of a 5-mm-wide and 25-mm-long strip of thin filter paper into the lower conjunctival sac while the other end hangs over the edge of the lower lid (the Schirmer test). The tears wet the strip of filter paper, producing a moisture front. After 5 min, the moistened area extends for a length of approximately 15 mm in normal persons. An extent of less than 10 mm is suggestive of hypolacrima. This test is used mainly to detect the dry eyes (keratoconjunctivitis sicca) of the Sjögren syndrome, but it may also be helpful in fully studying various autonomic neuropathies.
Tests of Bladder, Gastrointestinal, and Penile Erectile Function
Bladder function is best assessed by the cystometrogram, which measures intravesicular pressure as a function of the volume of saline solution permitted to flow by gravity into the bladder. The rise of pressure as 500 mL of fluid is allowed to flow gradually into the bladder, the emptying contractions of the detrusor, and the volume at which the patient reports a sensation of bladder fullness can be recorded by a manometer. (A detailed account of cystometric techniques can be found in the monograph of Krane and Siroky.) A simple way of determining bladder atony (prostatic obstruction and overdistention having been excluded) is to measure the residual urine (by catheterization of the bladder) immediately after voluntary voiding or to estimate its volume by ultrasound imaging.
Disorders of gastrointestinal motility are readily demonstrated radiologically. In dysautonomic states, a barium swallow may disclose a number of abnormalities, including atonic dilatation of the esophagus, gastric atony and distention, delayed gastric emptying time, and a characteristic small bowel pattern consisting of an increase in frequency and amplitude of peristaltic waves and rapid intestinal transit. A barium enema may demonstrate colonic distention and a decrease in propulsive activity. Sophisticated manometric techniques are now available for the measurement of gastrointestinal motility (see Low et al).
Nocturnal penile tumescence is recorded in some sleep laboratories and may be used as an ancillary test of sacral autonomic (parasympathetic) innervation.
Pharmacologic Tests of Autonomic Function
After examining the pupils in ambient light, bright light, and low light to determine if one has lost sympathetic or parasympathetic innervation, pharmacologic tests can be used to refine diagnosis. Part of the rationale behind these special tests is the “Cannon law,” or the phenomenon of denervation hypersensitivity, in which an effector organ, 2 to 3 wk after denervation, becomes hypersensitive to its particular neurotransmitter substance and related drugs. In clinical testing, an agent is instilled into both conjunctival sacs and the nonmiotic pupil is used as a control to compare the one suspect of being involved by Horner syndrome.
Relatively recently, the weak direct sympathetic agonist apraclonidine has been used most widely to demonstrate that miosis is due to sympathetic denervation of the pupil. It reverses miosis that is due to a central or a peripheral lesion and is easier to obtain then older agents. A positive test, reversal of miosis, depends on the denervation hypersensitivity that develops after several days or more of the presence of the Horner syndrome. If there is a negative result, no enlargement of the pupil, the miosis is probably physiologic. The drug has the additional advantage of often reversing the ptosis of Horner syndrome (see Chap. 13 and Fig. 13-10 for discussion). The drug may cause respiratory suppression in children and is avoided.
Once the presence of a genuine Horner syndrome has been established, it is possible to differentiate pre- from postganglionic (superior cervical ganglion) sympathetic denervation of the pupil by instilling 1 percent hydroxyamphetamine; its effect depends on the presence of existing norepinephrine in the end terminals of the nerves that innervate the iris. Failure to dilate indicates a postganglionic lesion.
Another test, now used mostly in children, in whom apraclonidine represents a risk, is the topical application into the conjunctival sac of a 4 to 10 percent cocaine solution that potentiates the effects of NE by preventing its reuptake. A normal response to cocaine consists of pupillary dilatation. In sympathetic denervation caused by lesions of the post- or preganglionic fibers, no change in pupillary size occurs because no transmitter substance is available and the cocaine has no substrate to potentiate. The reason for lack of response in chronic preganglionic lesions is presumed to be a depletion of NE in the postganglionic fibers. In cases of central sympathetic lesions, slight mydriasis may occur.
The intracutaneous injection of 0.05 mL of 1:1,000 histamine normally causes a 1-cm wheal after 5 to 10 min. This is surrounded by a narrow red areola, which in turn, is surrounded by an erythematous flare that extends 1 to 3 cm beyond the border of the wheal. A similar “triple response” follows the release of histamine into the skin as the result of a scratch. It can be elicited in sensitive individuals by scratching the skin (dermatographia).
The wheal and the deeply colored red areola are caused by the direct action of histamine on blood vessels in response to local injury, while the flare depends on the integrity of the axon reflex. This axon reflex is mediated by antidromic stimulation of small sensory C fibers that results in the release by the same fibers of various vasoactive substances such as bradykinin and substance P. Destruction of the dorsal root ganglion, but not the dorsal root, eliminates the flare. The flare component is influenced centrally through a yet unknown mechanism. In familial dysautonomia, the flare response to histamine and to scratch is absent. It may also be absent in peripheral neuropathies that involve sympathetic nerves (e.g., diabetes, alcoholic–nutritional disease, Guillain-Barré disease, amyloidosis, porphyria). The quantitative sudomotor response to topical acetylcholine, described earlier, is preferred for its sensitivity and accuracy but requires special equipment.
The dermatographic wheal and flare response may be lost below the level of a recent cord injury but returns over days or longer, comparable to recovery from spinal shock.
Pressor Infusion and Other Direct Cardiovascular Tests
While these are not parts of the routine laboratory evaluation of autonomic nervous system disease, they nonetheless present interesting physiologic information. The infusion of NE causes a rise in blood pressure, which is usually more pronounced for a given infusion rate in dysautonomic states than it is with normal subjects. In many instances, for example, the Guillain-Barré syndrome, the excessive rise in blood pressure is thought to be more a result of inadequate muting of the hypertension by baroreceptors than it is a reflection of true denervation hypersensitivity, that is, it reflects dysfunction of the afferent limb of the reflex arc. In patients with familial dysautonomia, the infusion of NE produces erythematous blotching of the skin, like that which may occur under emotional stress, probably representing an exaggerated response to endogenous NE.
The infusion of angiotensin II into patients with idiopathic orthostatic hypotension also causes an exaggerated blood pressure response. A similar response to methacholine and NE has been interpreted as a denervation hypersensitivity to neurotransmitter or related substances. A different mechanism must be invoked for the blood pressure response induced by angiotensin; perhaps it is caused by a defective baroreceptor function.
The integrity of autonomic innervation of the heart can be evaluated by the intramuscular injection of atropine, ephedrine, or neostigmine while the heart rate is monitored. Normally, the intramuscular injection of 0.8 mg of atropine causes tachycardia as a result of a parasympathetic block and a withdrawal of vagal tone. No such change occurs in cases of parasympathetic (vagal) denervation of the heart, the most common such conditions being diabetes and the Guillain-Barré syndrome and the most dramatic being the brain death state, in which there is no longer any tonic vagal activity to be ablated by atropine.
Laboratory methods are available for the measurement of NE and dopamine β-hydroxylase in the serum. Normally, when a person changes from a recumbent to a standing position, the serum NE level rises two- or threefold. In patients with central and peripheral autonomic failure, there is little or no elevation on standing or with exercise. The dopamine β-hydroxylase enzyme is deficient in patients with a rare form of sympathetic dysautonomia.
In summary, the noninvasive tests listed in Table 25-1 and described earlier are quite adequate for the clinical testing of autonomic function. Low has emphasized that the most informative tests are those that are quantitative and have been standardized and validated in patients with both mild and severe autonomic disturbances. At the bedside, the most convenient ones are measurement of orthostatic heart rate and blood pressure changes, blood pressure response to the Valsalva maneuver, estimation of heart-rate changes with deep breathing, pupillary responses to light and dark, and a rough estimate of sweating of the palms and soles and with lesions of the spinal cord, on the trunk. The results of these tests and the clinical situation will determine whether further testing is needed.
CLINICAL DISORDERS OF THE AUTONOMIC NERVOUS SYSTEM
Acute Autonomic Neuropathies (Pandysautonomia)
Since this condition was first reported by Young and colleagues in 1975, many more cases in both adults and children have been placed on record. Over a period of a week or a few weeks with or without a preceding systemic or respiratory infection, the patient develops some combination of anhidrosis, orthostatic hypotension, paralysis of pupillary reflexes, loss of lacrimation and salivation, erectile dysfunction, impaired bladder and bowel function (urinary retention, postprandial bloating, and ileus or constipation), and loss of certain pilomotor and vasomotor responses in the skin (flushing and heat intolerance). Fatigue, sometimes severe, is a prominent complaint in most patients, and abdominal pain and vomiting in others. A few develop sleep apnea or the syndrome of inappropriate secretion of antidiuretic hormone (SIADH), leading to hyponatremia. The cerebrospinal fluid (CSF) protein is normal or slightly increased.
Clinical and laboratory findings indicate that both the sympathetic and parasympathetic parts of the autonomic nervous system are affected, mainly at the postganglionic level. Somatosensory and motor nerve fibers appear to be spared or are affected to only a slight extent, although many patients complain of paresthesias, and tendon reflexes are frequently lost. In one of the patients described by Low and colleagues, there was physiologic and morphologic (sural biopsy) evidence of loss of small myelinated and unmyelinated somatic fibers and foci of epineurial mononuclear cells; in other cases, sural nerve fiber counts have been normal; and in an autopsied case, in which there had also been sensory loss, there was lymphocytic infiltration in sensory and autonomic nerves (Fagius et al). The original patient described by Young and colleagues and most of the other patients reported with pure dysautonomia are said to have recovered completely or almost so within several months, but many of our patients have been left with disordered gastrointestinal and sexual functions. In addition to an idiopathic form of autonomic paralysis, some cases are postinfectious, and there is a similar but rare paraneoplastic form (see Chap. 30 under “Paraneoplastic Sensory Neuronopathy”). Antibodies against ganglionic acetylcholine receptors have been found in half of idiopathic cases and one-quarter of paraneoplastic ones (Vernino et al).
Some children with this disease and a few adults have had a syndrome of predominantly cholinergic dysautonomia with pain and dysesthesias (Kirby et al); there is little or no postural hypotension and the course has been more chronic than that in cases of complete dysautonomia described earlier.
In view of the identical autonomic disturbances in the Guillain-Barré syndrome and the high incidence of minor degrees of weakness, reflex loss, CSF protein elevation, and especially paresthesias, it is likely that pure pandysautonomia is also an immune-mediated polyneuropathy affecting the autonomic fibers within peripheral nerves, in most ways comparable to the Guillain-Barré syndrome. The aforementioned autopsy findings reported by Fagius and coworkers support such a relationship. In animals, autonomic paralysis has been produced by injection of extracts of sympathetic ganglia and Freund’s adjuvant (Appenzeller et al), similar to the experimental immune neuritis that is considered as an animal model of the Guillain-Barré syndrome.
An acquired form of orthostatic intolerance, referred to as sympathotonic orthostatic hypotension (Polinsky et al), may represent another variant or partial form of autonomic paralysis. In this syndrome, unlike the common forms of orthostatic hypotension (see later), the fall in blood pressure is accompanied by tachycardia. Hoeldtke and colleagues, who described 4 such patients, found that the vasomotor reflexes and NE production were normal; these investigators were inclined to attribute the disorder to a process affecting lower thoracic and lumbar sympathetic neurons. Its relationship to the entity of postural orthostatic tachycardia syndrome (POTS) discussed in Chap. 17 and to the orthostatic intolerance associated with the chronic fatigue syndrome is uncertain. Individual cases of POTS have been associated with mutations or epigenetic alterations in the norepinephrine transporter gene (Shannon and colleagues, 2005). Some instances of orthostatic intolerance appear as part of the asthenia–anxiety disorders in which the autonomic changes may represent sympathetic overactivity in susceptible individuals.
There are several reports of improvement of pandysautonomia after intravenous gamma globulin infusion, but these are difficult to judge as many patients improve spontaneously over the same time frame, usually many months. In addition, plasma exchange has been used with apparent benefit in a patient with antibodies against the ganglionic acetylcholine receptor (Schroeder et al).
As more experience accumulated over years, it became apparent that acute autonomic neuropathies represent a spectrum of disorders and majority are likely immune-mediated. These disorders include acute autoimmune ganglionopathy—idiopathic or paraneoplastic, (previously called panautonomic neuropathy or pandysautonomia) characterized by severe and widespread sympathetic and parasympathetic failure. Other forms of acute autonomic neuropathies are acute cholinergic neuropathy, Guillain-Barré syndrome, botulism, porphyria, drug-induced or toxic. Restricted forms of acute autonomic neuropathies may results in postural tachycardia syndrome or motility disorders. Some patients with acute autonomic neuropathies have autoantibodies to the A3 acetylcholine receptor. Somatic involvement of variable severity is seen in majority of acute autonomic neuropathies.
Lambert-Eaton myasthenic syndrome
One of the characteristic features of the fully developed Lambert-Eaton myasthenic syndrome, which is discussed in Chap. 46, is dysautonomia, characterized by dryness of the mouth, erectile dysfunction, difficulty in starting the urinary stream, and constipation. Presumably, circulating antibodies against the voltage-gated calcium channel interfere with the release of ACh at both muscarinic and nicotinic sites.
Multiple System Atrophy and Pure Autonomic Failure
The clinical state of idiopathic orthostatic hypotension is now known to be caused by at least two conditions (See Also Chaps. 17 and 38). One is a degenerative disease of middle and late adult life, first described by Bradbury and Eggleston in 1925 and designated by them as idiopathic orthostatic hypotension and by subsequent authors, “primary autonomic failure.” In this disorder, the lesions involve mainly the postganglionic sympathetic neurons (Petito and Black); the parasympathetic system is relatively spared and the CNS is uninvolved. In the second more common disorder that is now classified as a multiple system atrophy, described initially by Shy and Drager, the preganglionic lateral horn neurons of the thoracic spinal segments degenerate; these changes are responsible for the orthostatic hypotension. Later, signs of basal ganglionic or cerebellar disease or both are added as discussed later and in Chaps. 17 and 38 but a few cases remain as a pure autonomic failure. In both types of orthostatic hypotension, anhidrosis, erectile dysfunction and atonicity of the bladder may be conjoined, but orthostatic fainting is the main problem.
The clinical differentiation of these two types of orthostatic hypotension depends largely on the appearance, with time, of associated CNS signs as described later. The distinction between the sympathetic postganglionic and the central preganglionic types of disease is also based on pharmacologic and neurophysiologic evidence, but it must be emphasized that the results of these tests do not always conform to clinical expectations from the examination. Nonetheless, Cohen and associates, who studied the postganglionic sudomotor and vasomotor functions of 62 patients with IOH, found that the signs of postganglionic denervation were uncommon in patients classified as having the central type.
In the postganglionic type of autonomic failure, plasma levels of NE are subnormal while the patient is recumbent because of failure of the damaged nerve terminals to synthesize or release catecholamines. When the patient stands, the NE levels do not rise, as they do in a normal person. Also, in this type, there is denervation hypersensitivity to infused NE. In the central preganglionic (Shy-Drager) type, the resting NE levels in the plasma are normal but again, on standing, there is no rise, and the response to exogenously administered NE is normal. In both types, the plasma levels of dopamine β-hydroxylase, the enzyme that converts dopamine to NE, are subnormal (Ziegler et al). The use of these neurochemical tests in clinical practice is difficult and the data in the literature are inconsistent. Low’s monograph should be consulted for procedural details.
Pathologic studies have disclosed the central type of autonomic failure to be somewhat heterogeneous. Oppenheimer, who collected all the reported central cases with complete autopsies, found that they fell into two groups: (1) that which was designated by Adams as striatonigral degeneration or, later, Shy-Drager syndrome, where autonomic failure was associated with a parkinsonian syndrome and often with the presence of cytoplasmic inclusions in sympathetic neurons, and (2) another with involvement of the striatum, cerebellum, pons, and medulla but without inclusions, formerly designated olivopontocerebellar degeneration (there are now reported to be glial and neuronal cytoplasmic inclusions in all these cases). Both conditions are now referred to as multiple system atrophy, the term introduced by Oppenheimer, the first type, MSA-P to denote the parkinsonism and the second type, MSA-C reflecting cerebellar degeneration as discussed in Chap. 38. If the process remains purely an autonomic failure, MSA-A is used.
In all forms of multiple system atrophy, the autonomic failure is attributable to degeneration of lateral horn cells of the thoracic cord. There is also a degeneration of nerve cells in the vagal nuclei as well as nuclei of the tractus solitarius, locus ceruleus, and sacral autonomic nuclei, accounting for laryngeal abductor weakness (laryngeal paralysis and stridor are features in some cases), incontinence, and erectile dysfunction. NE and dopamine are depleted in the hypothalamus (Spokes et al). The sympathetic ganglia have usually been normal. In Parkinson disease, where fainting is sometimes a problem, Lewy bodies are found in degenerating sympathetic ganglion cells but the medications used for treatment also exaggerate hypotension.
Treatment of orthostatic hypotension consists of adequate hydration (at least 1.5 L of fluids per day) with high salt intake, up 8 g of sodium per day, small and frequent meals (to reduce postprandial hypotension) and compression stockings or corset. Fainting can sometimes be avoided by the countermaneuvers of having the patient tightly cross his legs upon standing. Medical treatment can be initiated if nonmedical approaches fail. The peripherally acting alpha agonist, midodrine can be started at 2.5 mg q4h, slowly raising the dose to 5 mg q4h, taking the last dose before about 7 p.m. to void supine hypertension while asleep. The mineralocorticoid fludrocortisone acetate (Florinef) alleviates orthostatic hypotension by volume expansion due to the sodium retention by kidneys. Florinef can be started at dose 0.1 mg daily which may be slowly (over weeks) titrated up 0.9 mg daily. Fludrocortisone may cause hypokalemia and should be used cautiously in patients with severe supine hypertension; its effect may take up to 2 weeks to be manifest so rapid elevation of the dose is not advised. Pyridostigmine stimulates sympathetic ganglia and at doses 30 to 60 mg twice to thrice a day was also reported to be effective in treatment of orthostatic hypotension. Compared to florinef and midodrin, pyridostigmine is less potent pressor but it is much less likely causing supine hypertension. Pyridostigmine also may help to reduce constipation. A newer addition is droxidopa that is a prodrug to the neurotransmitter norepinephrine, acting both centrally and peripherally. Northera is usually started at the dose 100 mg three times a day which can be titrated up to 600 mg three times a day. Northera also increases risk of supine hypertension.
Peripheral Neuropathy With Neurogenic Orthostatic Hypotension
Impairment of autonomic function, of which orthostatic hypotension is the most serious feature, occurs as part of many acute and chronic peripheral neuropathies (e.g., diabetic, alcoholic–nutritional, amyloid, Guillain-Barré, heavy metal, toxic, and porphyric). Disease of the peripheral nervous system may affect the circulation in two ways: the nerves from baroreceptors may be affected, interrupting normal afferent homeostatic reflexes, or postganglionic efferent sympathetic fibers may be involved in their course in the spinal nerves. The severity of the autonomic failure need not parallel the degree of motor weakness. An additional feature of the acute dysautonomias is a tendency to develop hyponatremia, presumably as a result of dysfunction of afferent fibers from venous, right atrial, and aortic arch volume receptors; this elicits a release of antidiuretic hormone arginine vasopressin (AVP). These same stretch baroreceptors are implicated in the intermittent hypertension that sometimes complicates these acute neuropathies.
Of particular importance is the autonomic disorder that accompanies diabetic neuropathy. It presents as erectile dysfunction, constipation, or diarrhea (especially at night), hypotonia of the bladder, gastroparesis, and orthostatic hypotension, in some combination. Invariably, there are signs of a sensory polyneuropathy, consisting of a distal loss of vibratory and thermal-pain sensation and reduced or lost ankle reflexes; but again, the severity of affection of the two systems of nerve fibers may not be parallel. The pupils are often small and the amplitude of constriction to light is reduced (similar to Argyll Robertson pupils); this has been attributed to damage of cells in the ciliary ganglia. A curious syndrome or “insulin neuritis” has been described, in which, autonomic failure and painful sensory neuropathy arise at the time of rapid glycemic control (see Gibbons and Freeman, 2010).
Gastroparesis can be disabling, painful, and difficult to treat, for example, in diabetic autonomic neuropathy. Camilleri has reviewed the subject and outlined the defect in gastric emptying that interrelates with glucose metabolism and an unexplained association with psychiatric symptoms. Management is by altering nutritional intake and with metoclopramide for mild cases and additional domperidone, prochlorperazine, and erythromycin in severe ones.
Another polyneuropathy with unusually prominent dysautonomia is that caused by amyloidosis. Extensive loss of pain and thermal sensation is usually present; other forms of sensation may also be reduced to a lesser degree. Motor function is much less altered. Sympathetic function is more affected than parasympathetic. Iridoplegia (pupillary paralysis) and disturbances of other smooth muscle and glandular functions are variable. Diabetic and amyloid polyneuropathy are further described in Chap. 46.
Both the primary and secondary types of orthostatic hypotension are also discussed in connection with syncope in Chap. 17.
Familial Autonomic Neuropathy in Infants and Children (Riley-Day Syndrome) and Other Inherited Dysautonomias
Riley-Day syndrome is a disease of children, inherited as an autosomal recessive trait (See Also Chap. 43). The main symptoms are postural hypotension and lability of blood pressure, faulty regulation of temperature, diminished hearing, hyperhidrosis, blotchiness of the skin, insensitivity to pain, emotional lability, and cyclic vomiting. The tendon reflexes are hypoactive, and mild slowing of motor nerve conduction velocities is common. There is denervation sensitivity of the pupils and other structures. The main pathologic feature is a deficiency of neurons in the superior cervical ganglia and in the lateral horns of the spinal cord. Also, according to Aguayo and to Dyck and their colleagues, the number of unmyelinated nerve fibers in the sural nerve is greatly decreased. It is likely that this disease represents a failure of embryologic migration or formation of the first- and second-order sympathetic neurons. It is now known that this defect is the result of a mutation in the gene (IKBKAP) that codes for a protein (IKAP) that is currently considered to be associated with transcription regulation (Anderson et al). This results in a decrease in the amount of functional protein in autonomic neurons.
Autonomic symptoms are also a prominent feature of the small-fiber neuropathy of Fabry disease (alpha-galactosidase deficiency) as a result of the accumulation of ceramide in hypothalamic and intermediolateral column neurons (see “Fabry Disease” in Chap. 43).
Another inherited form of peripheral dysautonomia is characterized by severe pain in the feet on exercise and an autosomal dominant pattern of inheritance (Robinson et al). Bending, crouching, and kneeling increase stabbing pains in the feet. There is no sweat response to intradermal injection of 1 percent ACh and no autonomic fibers were found in punch biopsies of the skin. Systemic amyloidosis is the other type of peripheral neuropathy that has prominent features of autonomic failure.
Autonomic Failure in the Elderly
Orthostatic hypotension, a marker of autonomic sympathetic failure, is defined for research purposes as a reduction of systolic blood pressure of 20 mm Hg or more, or a drop in diastolic blood pressure of 10 mm Hg or more at the third minute of standing (See Also Chap. 28). Orthostatic hypotension is typically due to baroreflex failure. In the elderly, orthostatic hypotension commonly results from the use of medications. Neurogenic orthostatic hypotension results from a lesion in autonomic nervous system and is frequently seen in multiple system atrophy, Parkinson’s disease or diabetes.
It should be emphasized how prevalent orthostatic hypotension is in the elderly. Caird and coworkers reported that among individuals who were older than 65 years of age and living at home, 24 percent had a fall of systolic blood pressure on standing of 20 mm Hg; 9 percent had a fall of 30 mm Hg; and 5 percent had a fall of 40 mm Hg. An increased frequency of thermoregulatory impairment also has been documented. The elderly are also more liable to develop hypothermia and, when exposed to high ambient temperature, to hyperthermia. Loss of sweating of the lower parts of the body and increased sweating of the head and arms probably reflect a neuropathy or neuronopathy. The number of sensory ganglion cells decreases with age (de Castro). Erectile dysfunction and incontinence also increase with age, but these, of course, may be the result of a number of processes besides autonomic failure and many of the medications used to treat ailments that come with aging, such as hypertension, prostatic hypertrophy, depression, and impotence, have autonomic effects and can cause orthostatic hypotension.
It is of interest that an idiopathic type of small fiber neuropathy that occurs predominantly in elderly women (“burning hands and feet” syndrome) has no associated autonomic features (see Chap. 43).
Horner (Oculosympathetic) and Stellate Ganglion Syndromes
Interruption of postganglionic sympathetic fibers at any point along the internal carotid arteries or a lesion of the superior cervical ganglion results in miosis, drooping of the eyelid, and abolition of sweating over one side of the face; this constellation is the Horner, or more properly, Bernard-Horner syndrome (see also “Horner Syndrome” in (See Also Chap. 13). The same syndrome in less-obvious form may be caused by interruption of the preganglionic fibers at any point between their origin in the intermediolateral cell column of the C8-T2 spinal segments and the superior cervical ganglion or by interruption of the descending, uncrossed hypothalamospinal pathway in the tegmentum of the brainstem or cervical cord. The common causes are neoplastic or inflammatory involvement of the cervical lymph nodes or proximal part of the brachial plexus, surgical and other types of trauma to cervical structures (e.g., jugular venous catheters), carotid artery dissection, syringomyelic or traumatic lesions of the first and second thoracic spinal segments, and infarcts or other lesions of the lateral part of the medulla (Wallenberg syndrome). There is also an idiopathic variety that is in some cases hereditary. If a Horner syndrome develops early in life, the iris on the affected side fails to become pigmented and remains blue or mottled gray-brown (heterochromia iridis; see Fig. 13-10).
A lesion of the stellate ganglion, for example, compression by a tumor arising from the superior sulcus of the lung (Pancoast tumor), produces the interesting combination of a Horner syndrome and paralysis of sympathetic reflexes in the limb (the hand and arm are dry and warm). With preganglionic lesions, facial flushing may develop on the side of the sympathetic disorder; this is brought on in some instances by exercise (harlequin effect). The combination of segmental anhidrosis and an Adie pupil is sometimes referred to as the Ross syndrome; it may be abrupt in onset and idiopathic, or it may follow a viral infection.
Keane has provided data as to the relative frequency of the lesions causing oculosympathetic (Horner) paralysis. In 100 successive cases, 63 were of central type caused by brainstem strokes, 21 were preganglionic from trauma or tumors of the neck, 13 were postganglionic from miscellaneous causes, and in 3 cases the localization could not be determined (see Chap. 13 for further discussion).
The pupillary disturbances associated with oculomotor nerve lesions, the Adie pupil, and other parasympathetic and pharmacologic testing for sympathetic abnormalities of pupillary function are considered fully in Chap. 13 and in Table 13-6 with the accompanying text. Apraclonidine, 0.5 percent, has become the favored drug for diagnostic testing as noted earlier.
Sympathetic and Parasympathetic Paralysis in Tetraplegia and Paraplegia
Lesions of the C4 or C5 segments of the spinal cord, if complete, will interrupt suprasegmental control of both the sympathetic and sacral parasympathetic nervous systems. Much the same effect is observed with lesions of the upper thoracic cord (above T6). Lower thoracic lesions leave much of the descending sympathetic outflow intact, only the descending sacral parasympathetic control being interrupted. Traumatic necrosis of the spinal cord is the usual cause of these states, but they also may be a result of infarction, certain forms of myelitis, radiation damage, and tumors.
As discussed in greater detail in Chap. 42, the initial effect of an acute cervical cord transection is abolition of all sensorimotor reflex, and autonomic functions of the isolated spinal cord. The autonomic changes include hypotension, loss of sweating and piloerection, paralytic ileus and gastric atony, and paralysis of the bladder. The flare component of the axon reflex may be lost. Plasma epinephrine and NE are reduced. This state, known as spinal shock, usually lasts for several weeks as described in Chap. 42. The basic mechanisms are not known, but changes in neurotransmitters (catecholamines, enkephalins, endorphins, substance P, and 5-hydroxytryptamine) and their inhibitory activities are considered to play a role. Naloxone mitigates some of the aspects of spinal shock; this may be, at least in part, the result of release of preformed endogenous opioids from the distal axons that are separated from their cells of origin in the periaqueductal gray region. Once these endogenous substances are exhausted, the phenomenon of spinal shock ends (see Chap. 42).
After spinal shock dissipates, reflex sympathetic and parasympathetic functions return because the afferent and efferent autonomic connections within the isolated segments of the spinal cord are intact, although no longer under the control of higher centers. With cervical cord lesions, there is a loss of the sympathetically mediated cardiovascular changes in response to stimuli reaching the medulla. However, cutaneous stimuli (pinprick or cold) in segments of the body below the transection will raise the blood pressure. However, a fall in blood pressure is not compensated by sympathetic vasoconstriction. Hence tetraplegics are almost obligatorily prone to orthostatic hypotension. Pinching the skin below the lesion causes gooseflesh in adjacent segments. Heating the body results in flushing and sweating over the face and neck, but not in the trunk and legs, because of the loss of connections from the hypothalamus. Bladder and bowel, including their sphincters, which are at first flaccid, become automatic as spinal reflex control returns. There may be reflex penile erection or priapism and even rarely ejaculation. With lesions in the upper thoracic cord, similar but lesser degrees of labile blood pressure are seen; in several of our patients with destructive myelitis, a viral infection of fever brought out episodes of a drop in blood pressure to approximately 80/60 mm Hg and a subsequent rapid rise to 190/110 mm Hg.
After a time, the tetraplegic patient may develop a mass reflex in which flexor spasms of the legs and involuntary emptying of the bladder are associated with a marked rise in blood pressure, bradycardia, and sweating and pilomotor reactions in parts below the cervical segments (autonomic dysreflexia). These reactions may also be evoked by pinprick, passive movement, contactual stimuli of the limbs and abdomen, and pressure on the bladder. An exaggerated vasopressor reaction also occurs in response to injected NE. In such attacks, the patient experiences paresthesias of the neck, shoulders, and arms; tightness in the chest and dyspnea; pupillary dilatation; pallor followed by flushing of the face; sensation of fullness in the head and ears; and a throbbing headache. Plasma NE and dopamine rise slowly during the autonomic discharge. When such an attack is severe and prolonged, electrocardiographic changes may appear, sometimes with evidence of myocardial injury that has been attributed to direct catecholamine toxicity or, alternatively, to myocardial ischemia caused by increased afterload or to coronary vasospasm. Seizures and visual defects have also been observed, related to cerebral dysautoregulation. Clonidine, up to 0.2 mg tid, has been useful in preventing the hypertensive crises.
Acute Autonomic Crises (Sympathetic Storm)
Several toxic and pharmacologic agents such as cocaine and phenylpropanolamine are capable of producing abrupt overactivity of the sympathetic and parasympathetic nervous systems—severe hypertension and mydriasis coupled with signs of CNS excitation—sometimes including seizures. Tricyclic antidepressants in excessive doses are also known to produce autonomic effects, but in this case cholinergic blockade leads to dryness of the mouth, flushing, absent sweating, and mydriasis. The main concern with tricyclic antidepressant overdose is the development of a ventricular arrhythmia, also on an autonomic basis, presaged by prolongation of the QT interval on the ECG. Poisoning with organophosphate insecticides (e.g., Parathion), which have anticholinesterase effects, causes a combination of parasympathetic overactivity and motor paralysis (see discussion of poisonings in Chap. 41). A severe autonomic disturbance involving both postganglionic sympathetic and parasympathetic function is produced by ingestion of the rodenticide N-3-pyridylmethyl-N′-p-nitrophenylurea (PNU, Vacor). The exaggerated sympathetic state that accompanies tetanus—manifest by diaphoresis, mydriasis, and labile or sustained hypertension—has been attributed to circulating catecholamines.
Among the most dramatic syndromes of unopposed sympathetic-adrenal medullary hyperactivity occur in cases of severe head injury and with hypertensive cerebral hemorrhage. Three separate mechanisms of the hypersympathetic state are observed at different times after the injury or cerebral hemorrhage: an outpouring of adrenal catecholamines at the time of the ictus with acute hypertension and tachycardia; a brainstem-mediated vasopressor reaction (Cushing response, described in the following pages); and a later chronic phenomenon, consisting of episodes of extreme hypertension, profuse diaphoresis, and pupillary dilatation, usually arising during episodes of several minutes’ duration of rigid extensor posturing (the “diencephalic autonomic seizures” of Penfield, described later and in Chap. 34 in relation to head injury). Most patients who exhibit such paroxysms are decorticate from traumatic lesions of the deep cerebral white matter or from acute hydrocephalus (the likely explanation of Penfield’s and Jasper’s cases); in any case, they are clearly not epileptic. These attacks may be the result of the removal of inhibitory influences on the hypothalamus, creating, in effect, a hypersensitive decorticated autonomic nervous system.
Regarding the acute sympathetic reaction, experimental evidence suggests that nuclei in the caudal medullary reticular formation (reticularis gigantocellularis and parvocellularis) can precipitate severe hypertensive reactions. These nuclear centers are tonically inhibited by the NTS, which receives afferent input from arterial baroreceptors and chemoreceptors. Bilateral lesions of the NTS therefore produce extreme elevations in blood pressure, and this abrupt rise plays a role in the genesis of “neurogenic” pulmonary edema. These sympathetically mediated effects are eliminated by sectioning of the cervical spinal cord and by alpha-adrenergic blockade.
The Cushing response, reflex, triad, or “reaction,” as Cushing described it, occurs as a result of an abrupt increase in intracranial pressure. It consists of hypertension, bradycardia, and slow, irregular breathing elicited by the stimulation of mechanically sensitive regions in the paramedian caudal medulla (Hoff and Reis). Similar pressure-sensitive areas in the upper cervical spinal cord are also implicated in the Cushing response when intraspinal pressure is raised abruptly; a ventral medullary vasodepressor area that acts in the opposite manner has been found in animals. The proximate cause of the Cushing response is probably from mechanical distortion of the lower brainstem, either from a mass in the posterior fossa or, more often, from a large mass in one of the hemispheres or a subarachnoid hemorrhage that elevates the pressure within the fourth ventricle. Often, only the hypertensive component of the reaction occurs, with the systolic blood pressure reaching levels of 200 mm Hg, spuriously suggesting the presence of a pheochromocytoma or renal artery stenosis. The most severe instances of this type of centrally provoked hypertensive syndrome have occurred in children with cerebellar tumors who presented with headache and extreme systolic hypertension. Difficulty may arise in differentiating this response from hypertensive encephalopathy, especially from cases that derive from renovascular hypertension, which may likewise be accompanied by headache and papilledema. In differentiating these two, it is useful to note that primary hypertensive encephalopathy is associated with a tachycardia or normal heart rate and that systolic blood pressure levels above 210 mm Hg are attained only rarely in the Cushing response.
During episodes of intense sympathetic discharge of any type, there are alterations in the ECG, mainly in the ST segments and T waves; in extreme cases, evidence of myocardial damage can be observed. Both direct sympathetic innervation of the heart and the surge in circulating NE and cortisol are the cause of these findings. A similar hyperadrenergic mechanism has been proposed to explain sudden death from fright, asthma, status epilepticus, and cocaine overdose. Investigations by Schobel and colleagues had suggested that sustained sympathetic overactivity is responsible for the hypertension of preeclampsia, which may be considered in some ways as a dysautonomic state but this may be an oversimplification. Further information on these topics is contained in Chap. 34 and in the reviews by Samuels and Ropper.
A role has also been inferred for the ventrolateral medullary pressor centers in the maintenance of essential hypertension. Geiger and colleagues removed a looped branch of the posteroinferior cerebellar artery that had been apposed to the ventral surface of the medulla in 8 patients who had intractable essential hypertension; they found that 7 improved. Vascular decompression of cranial nerves has proved to be a credible therapeutic measure for hemifacial spasm and some cases of vertigo and trigeminal neuralgia, as discussed in Chap. 4, but the notion of vascular compression of the ventral medulla as a mechanism for typical essential hypertension requires confirmation before being accepted.
The Effects of Thoracolumbar Sympathectomy
Surgical resection of the thoracolumbar sympathetic trunk, widely used in the 1940s in the treatment of hypertension but now of historical interest, provided the clinician with the clearest examples of extensive injury to the peripheral sympathetic nervous system, though a similar defect had long been suspected in one type of primary orthostatic hypotension (see earlier). In general, bilateral thoracolumbar sympathectomy results in surprisingly few disturbances. Aside from loss of sweating over the denervated areas of the body, the most pronounced abnormality is an impairment of vasomotor reflexes. In the upright posture, faintness and syncope are frequent because of pooling of blood in the splanchnic bed and lower extremities. Although the blood pressure may fall steadily to shock levels, there is little or no pallor, nausea, vomiting, or sweating—the usual accompaniments of syncope. Bladder, bowel, and sexual function are preserved, though semen is sometimes ejaculated into the posterior urethra and bladder (retrograde ejaculation).
This disorder, characterized by episodic, painful blanching of the fingers and presumably caused by digital artery spasm, was first described by Raynaud in 1862. The appearance is of a triphasic sequence of color change of pallor, cyanosis, and subsequent rubor of the affected fingers or toes, but about one-third of such patients have no cyanosis. The episodes are brought on by cold or emotional stress and are usually followed by redness on rewarming. Numbness, paresthesia, and burning often accompany the color changes. It is a disease of early onset, the mean age in idiopathic cases being 14 years; it occurs in a number of clinical settings.
Although most cases are idiopathic, in about half there is an associated connective tissue disease, scleroderma being the main one (Porter et al). In these patients, mostly women with the onset of digital symptoms after age 30 years, the Raynaud phenomenon may antedate the emergence of scleroderma or another rheumatologic autoimmune disorder by many years; such disease usually develops within 2 years. In a small group, predominantly men, the syndrome is induced by local trauma, such as prolonged sculling on a cold day, and particularly by vibratory injury incurred by the sustained use of a pneumatic drill or hammer (a syndrome well known in quarry workers). Obstructive arterial disease—as might occur with the thoracic outlet syndrome, vasospasm because of drugs (ergot, cytotoxic agents, cocaine), previous cold injury (frostbite), and circulating cryoglobulins—is a less-common cause. Still, in 64 of 219 patients studied by Porter and coworkers, the Raynaud syndrome was classified as idiopathic, and most of our cases have been of this type. Formerly, the idiopathic form was called Raynaud disease; the type with associated disease is known as Raynaud phenomenon. The presence of distorted and proliferative capillaries in the nail bed, visible with an ophthalmoscope, has been used as a bedside aid to reveal cases of connective tissue disease.
Other processes seen by neurologists, foremost among them carpal tunnel syndrome, also cause cold sensitivity in the fingers. Attacks of digital pain and color change from vasculitis, atherosclerotic vascular occlusion, and other causes of occlusive vascular disease only superficially resemble the Raynaud phenomenon; a search for cryoprecipitable proteins (cryoglobulins) is another cause and a search for these proteins in the blood is appropriate.
Irrespective of the associated disease, one of two mechanisms seems to be operative in the pathogenesis—either an arterial constriction or a decrease in the intraluminal pressure. The former, in purest form, is observed in young women on exposure to cold and aggravated by emotional stress; a decrease in intraluminal pressure is associated with arterial obstruction. Treatment is directed to the associated conditions and prevention of precipitating factors. Cervicothoracic sympathectomy has not proved to be an effective measure.
Avoidance of cold exposure is an obvious strategy, as almost all affected patients have discovered by the time they see the physician. Drugs that cause vasoconstriction are interdicted (ergots, sympathomimetics, clonidine, and serotonin receptor agonists). Calcium channel blockers are most effective, nifedipine being the most widely used, in doses of 30 to 60 mg/d. Other treatments are summarized in the review by Wigley.
Erythromelalgia, first described by S. Weir Mitchell, is a condition in which the feet and lower extremities become red and painful on exposure to warm temperatures for prolonged periods (see the section on this disease in Chap. 10, where the clinical and genetic aspects of this illness are described).
Hyperhidrosis results from overactivity of sudomotor nerve fibers under a variety of conditions. It may occur as an initial excitatory phase of certain peripheral neuropathies (e.g., because of arsenic or thallium) and be followed by anhidrosis; it is one aspect of the reflex sympathetic dystrophy pain syndromes (see Chap. 7). This is also observed as a localized effect in painful mononeuropathies (causalgia) and diffusely in a number of painful polyneuropathies (“burning foot” syndrome). A type of nonthermoregulatory hyperhidrosis may occur in spinal paraplegics, as mentioned earlier. Loss of sweating in one part of the body may require a compensatory increase in normal parts—for example, the excessive facial and upper truncal sweating that occurs in patients with transection of the high thoracic cord.
Localized hyperhidrosis may be a troublesome complaint in some patients. One variety, presumably of congenital origin, affects the palms. The social embarrassment of a “succulent hand” or a “dripping paw” is often intolerable. It is taken to be a sign of nervousness, although many persons with this condition disclaim all other anxiety symptoms. Cold, clammy hands are common in individuals with anxiety; indeed, this has been a useful sign in distinguishing an anxiety state from hyperthyroidism, in which the hands are also moist but warm. Extirpation of T2 and T3 sympathetic ganglia relieves the more severe cases of palmar sweating; a Horner syndrome does not develop if the T1 ganglion is left intact. In other cases, the hyperhidrosis affects mainly the feet or the axillae. Treatment with local injections of botulinum toxin has been useful and is now favored over ablative procedures.
Anhidrosis in restricted skin areas is a frequent and useful finding in peripheral nerve disease. It is caused by the interruption of the postganglionic sympathetic fibers, and its boundaries can be mapped by means of the sweat tests described earlier in the chapter. The loss of sweating corresponds to the area of sensory loss. In contrast, sweating is not affected in restricted spinal root disease because there is much intersegmental mixing of the preganglionic axons once they enter the sympathetic chain and there are no preganglionic autonomic fibers in the roots below L3.
A postinfectious anhidrosis syndrome has been described, sometimes accompanied by mild orthostatic hypotension. This process is probably a limited form of the “pure pandysautonomia” described earlier. Corticosteroids are said to be beneficial but the process is so infrequent that there are no dependable data.
Other rare but interesting disorders of sweating are Ross syndrome, Adie pupil (see Chap. 13), areflexia and segmental anhidrosis with compensatory hyperhydrosis in other regions of the body, and idiopathic pure sudomotor failure, characterized by urticaria, generalized anhidrosis and elevated IgE; in this syndrome there is no sweating to thermoregulatory needs but preserved sweating with emotional stimuli.
Disturbances of Bladder Function
With regard to the neurologic diseases that cause bladder dysfunction, multiple sclerosis, usually with urinary urgency, is by far the most common. In Fowler’s clinic, other spinal cord disorders accounted for 12 percent of cases, degenerative diseases (Parkinson disease and multiple system atrophy) for 14 percent, and frontal lobe lesions for 9 percent. These data and the physiologic principles elaborated earlier enable one to understand the effects of the following lesions on bladder function (see Fig. 25-4):
Complete destruction of the cord below T12
This occurs with lesions of the conus, as from trauma, myelodysplasias, tumor, venous angioma, and necrotizing myelitis. The bladder is paralyzed for voluntary and reflex activity and there is no awareness of the state of fullness; voluntary initiation of micturition is impossible; the tonus of the detrusor muscle is abolished and the bladder distends as urine accumulates until there is overflow incontinence; voiding is possible only by the Credé maneuver, that is, lower abdominal compression and abdominal straining. Usually the anal sphincter and colon are similarly affected, and there is “saddle” anesthesia and abolition of the bulbocavernosus and anal reflexes as well as the tendon reflexes in the legs. The cystometrogram shows low pressure and no emptying contractions.
Disease of the sacral motor neurons in the spinal gray matter, the anterior sacral roots, or peripheral nerves innervating the bladder
The typical causes of this configuration are lumbosacral meningomyelocele and the tethered cord syndrome, in effect, a lower motor neuron paralysis of the bladder. The disturbance of bladder function is the same as above, except that sacral and bladder sensation are intact. Other causes of cauda equina disease are compression by epidural tumor or disc, neoplastic meningitis, and radiculitis from herpes or cytomegalovirus (Elsberg syndrome). It is noteworthy that a hysterical patient can suppress motor function and suffer a similar distention of the bladder (see later).
Interruption of sensory afferent fibers from the bladder
Diabetes and tabes dorsalis are typical causes, leaving the motor nerve fibers unaffected. This is a primary sensory bladder paralysis. The disturbance in function is the same as in the two processes earlier. Although a flaccid (atonic) paralysis of the bladder may be purely motor or sensory, as described earlier, in most clinical situations there is interruption of both afferent and efferent innervation, as in cauda equina compression or severe polyneuropathy. Neuropathies affecting mainly the small fibers are the ones usually implicated (diabetes, amyloid, etc.), but urinary retention also occurs in certain acute neuropathies such as Guillain-Barré syndrome.
Upper spinal cord lesions, above T12
Such lesions result in a reflex neurogenic (spastic) bladder. In addition to multiple sclerosis and traumatic and compressive myelopathies, which are the most common causes, myelitis, neuromyelitis optica, spondylosis, dural arteriovenous fistula, syringomyelia, and tropical spastic paraparesis may cause a bladder disturbance of this type. If the cord lesion is of sudden onset, the detrusor muscle suffers the effects of spinal shock. At this stage, urine accumulates and distends the bladder to the point of overflow. This overflow incontinence is the result of vesicular pressure exceeding the opening pressure of the sphincter in an areflexic bladder. As the effects of spinal shock subside, the detrusor usually becomes reflexively overactive, and because the patient is unable to inhibit the detrusor and control the external sphincter, urgency, precipitant micturition, and incontinence result. Incomplete lesions result in varying degrees of urgency in voiding. With slowly evolving processes involving the upper cord, such as multiple sclerosis, the bladder spasticity and urgency worsen with time and incontinence becomes more frequent. In addition, initiation of voluntary micturition is impaired and bladder capacity is reduced. Bladder sensation depends on the extent of involvement of sensory tracts. Bulbocavernosus and anal reflexes are preserved. The cystometrogram shows uninhibited contractions of the detrusor muscle in response to small volumes of fluid. Most puzzling to the authors have been cases of cervical cord injury in which reflex activity of the sacral mechanism does not return; the bladder remains hypotonic.
Stretch injury of the bladder wall
This occurs with anatomic obstruction at the bladder neck and occasionally with psyhcogenic retention of urine. Repeated overdistention of the bladder wall often results in varying degrees of decompensation of the detrusor muscle and permanent atonia or hypotonia, although the evidence for this mechanism is uncertain. The bladder wall becomes fibrotic and bladder capacity is greatly increased. Emptying contractions are inadequate, and there is a large residual volume even after the Credé maneuver (manual abdominal compression) and strong contraction of the abdominal muscles. As with motor and sensory paralyses, the patient is subject to cystitis, ureteral reflux, hydronephrosis and pyelonephritis, and calculus formation.
Nonpsychogenic urinary retention in women
Fowler has described a disorder of bladder function in women, in which there is impaired relaxation of the periurethral striated muscle, as recorded by EMG. The complex repetitive discharges that are characteristic of the disorder are similar to, but distinctive from those seen in myotonia and cannot be voluntarily simulated. Fowler has theorized that the disorder is an efferent denervation of the detrusor muscle, which is coincident with the clinical observation that bladder distention in these patients is usually painless. This disorder has been seen in association with polycystic ovarian syndrome. Most young women with painless dilation of the bladder are diagnosed as having a psychogenic cause. The existence of a bona fide organic disorder may reduce stigma and facilitate treatment in some such patients. Some patients have been successfully treated with a sacral nerve stimulator.
Frontal lobe incontinence
There is a supranuclear type of hyperactivity of the detrusor that results in precipitant voiding. If the lesions are extensive enough in the frontal lobes, the patient, because of an abulic or confused mental state, may additionally be unconcerned by the subsequent incontinence. The bladder itself and the associated sphincter functions are normal as would be seen in a precontinent child. These types of frontal lobe incontinence are considered in the description of abnormalities consequent to frontal lobe damage in Chap. 21.
Brainstem lesions influencing bladder function
As discussed earlier, a role for pontine centers in human micturition has been inferred from animal experiments. The existence of a well-delineated pontine nucleus for micturition is controversial (Barrington nucleus). MRI studies by Sakakibara and colleagues have documented isolated pontine lesions as a cause of several different types of micturition difficulties.
Therapy of Disordered Micturition
Several drugs have been used in the management of flaccid and spastic disturbances of bladder function. In the case of a flaccid paralysis, bethanechol (Urecholine) produces contraction of the detrusor by direct stimulation of its muscarinic cholinergic receptors. In spastic paralysis, the detrusor can be relaxed by propantheline (Pro-Banthine, 15 to 30 mg tid), which acts as a muscarinic antagonist, and by oxybutynin (Ditropan, 5 mg bid or tid), which acts directly on the smooth muscle and also has a muscarinic antagonist action. Atropine, which is mainly a muscarinic antagonist, only partially inhibits detrusor contraction.
More recently, alpha1-sympathomimetic–blocking drugs such as terazosin, doxazosin, and tamsulosin have been used to relax the urinary sphincter and facilitate voiding. Their widest use has been in men with prostatic hypertrophy, but they may be beneficial in patients with dyssynergia of the sphincter (failure of the sphincter to open when the detrusor contracts) from neurologic disease. Several other drugs may be useful in the treatment of neurogenic bladder but can be used rationally only on the basis of sophisticated urodynamic investigations (Krane and Siroky).
Often the patient must resort to intermittent self-catheterization, which can be safely carried out with scrupulous attention to sterile technique (washing hands, disposable catheter, etc.). Some forms of chronic antibiotic therapy and acidification of urine with vitamin C (1,000 g/d) are practical aids, but their use has gone through cycles of popularity based on various studies with differing results. In selected paraplegic patients, the implantation of a sacral anterior root stimulator may prove to be helpful in emptying the bladder and achieving continence (Brindley et al).
Disturbances of Bowel Function
Ileus from spinal shock, reflex neurogenic colon, and sensory and motor paralysis are all recognized clinical entities. The colon, stomach, and small intestine may be hypotonic and distended and the anal sphincters lax, either from deafferentation, deefferentation, or both. The anal and, in the male, the bulbocavernosus reflex may be abolished. Defecation may be urgent and precipitant with higher spinal and cerebral lesions. Because the same spinal segments and nearly the same spinal tracts subserve bladder and bowel function, meningomyeloceles and other cauda equina and spinal cord diseases often cause so-called double incontinence. Fecal incontinence is less frequent than urinary incontinence, however, because the bowel is less-often filled and its content is usually solid.
Bowel dysmotility, mainly by way of ileus may be a prominent feature of immune neuropathies such as Guillain-Barré syndrome (see Chap. 43), pure pandysautonomia, and severe diabetic autonomic neuropathy discussed earlier. In a few cases of the latter, antibodies against the alpha subunit of the ganglionic acetylcholine receptor has been found by Vernino and colleagues. Systemic diseases may affect the colonic sphincters; examples are myotonic dystrophy and scleroderma, which may weaken the internal sphincter, and polymyositis and myasthenia gravis, which may impair the function of the external sphincter and allow bowel gas to escape (Schuster). The inability to control flatulence may be an early sign of skeletal muscle sphincteric weakness in myasthenia. Also, sphincteric damage may complicate hemorrhoidectomy.
In recent years there has been considerable interest in weakness of the muscles of the pelvic floor as a cause of double incontinence, especially in the female. Also, it has been suggested that paradoxical contraction of the puborectus and external anal sphincter may be a cause of severe constipation (anismus). Extreme degrees of descent of the pelvic floor are believed to injure the pudendal nerves, as reflected in prolonged terminal latencies in nerve conduction studies.
Many cases of ileus, even to the extent of megacolon, have a pharmacologic basis, being a result of the use of drugs that paralyze the parasympathetic system or narcotics that have a direct effect on the motility of gastrointestinal smooth muscle.
The serotonin receptor agonist cisapride had been used in partially restoring gastrointestinal motility in some cases of neurogenic ileus as, for example, the early stages of the Guillain-Barré syndrome and in pediatric bowel diseases. Because of ventricular arrhythmias and a few cases of sudden cardiac death, its administration is currently allowed only by experienced pediatric gastroenterologists.
Congenital Megacolon (Hirschsprung Disease)
This is a rare disease affecting mainly male infants and children. It is caused by a congenital absence of ganglion cells in the myenteric plexus. The internal anal sphincter and rectosigmoid are involved most often and are the parts affected in restricted forms of Hirschsprung disease (75 percent of cases), but the aganglionosis is sometimes more extensive. The aganglionic segment of the bowel is constricted and cannot relax, thus preventing propagation of peristaltic waves, which, in turn, produces retention of feces and massive distention of the colon above the aganglionic segment. Enterocolitis is the most serious complication and is associated with a high mortality. Some cases of megaloureter are attributed to a similar defect.
Hirschsprung disease in most cases has been traced to a mutation of the RET oncogene and perhaps to polymorphisms in other genes; the variability in clinical severity corresponds to polymorphisms in the responsible gene. Other genes, such as the one that codes for the endothelin receptor, are implicated in a small group with the disease. There are several other familial diseases that may manifest as an enteric neuropathy including an unusual mitochondrial disorder discussed in Chap. 36, Allgrove syndrome, and an entity termed familial visceral myopathy.
Disturbances of Sexual Function
Sexual function in the male, which is not infrequently affected in neurologic disease, may be divided into several parts: (1) sexual impulse, drive, or desire, referred to as libido, discussed in Chap. 24; (2) penile erection, enabling the act of sexual intercourse (potency); and (3) ejaculation of semen by the prostate through the urethra.
The arousal of libido in men and women may result from a variety of stimuli, some purely psychic. Neocortical influences referable to sex involve the limbic system and are transmitted to the hypothalamus and spinal centers. The suprasegmental pathways traverse the lateral funiculi of the spinal cord near the corticospinal tracts to reach sympathetic and parasympathetic segmental centers. Penile erection is effected through sacral parasympathetic motor neurons (S3 and S4), the nervi erigentes, and pudendal nerves. There is some evidence also that a sympathetic outflow from thoracolumbar segments (originating in T12-L1) via the inferior mesenteric and hypogastric plexuses can mediate psychogenic erections in patients with complete sacral cord destruction. Activation from these segmental centers opens vascular channels between arteriolar branches of the pudendal arteries and the vascular spaces of the corpora cavernosa and corpus spongiosum (erectile tissues), resulting in tumescence. Detumescence occurs when venous channels open widely. Ejaculation involves rhythmic contractions of the prostate, compressor (sphincter) urethrae, and bulbocavernosus and ischiocavernosus muscles, which are under the control of both the sympathetic and parasympathetic centers. Afferent segmental influences arise in the glans penis and reach parasympathetic centers at S3 and S4 (reflexogenic erections). Figure 25-7 shows the organization of this neural system and the locations of lesions that can abolish normal erectile function. Similar neural arrangements exist in females.
The pathways involved in human penile erection. See text for details. (Reproduced by permission from Weiss.)
The different aspects of sexual function may be affected separately. Loss of libido may depend on both psychic and somatic factors. It may be complete, as in old age or in medical and endocrine diseases, or it may occur only in certain circumstances or in relation to certain situations. In the latter case, which is a result of psychologic factors, reflex penile erection during rapid eye movement (REM) sleep, and even emission of semen, may occur.
Sexual desire can be altered in the opposite direction, that is, it may be excessive. This, too, is usually psychologic or psychiatric in origin, as in manic states, but sometimes it occurs with neurologic disease, such as encephalitis and tumors that affect the diencephalon, septal region, and temporal lobes; with the dementias; and as a result of certain medications such as l-dopa, as discussed in Chap. 24. In the instances of neurologic diseases with hypersexuality, there are usually other signs of disinhibited behavior as well.
On the other hand, sexual drive may be present but penile erection impossible to attain or sustain. The most common cause of erectile dysfunction is a depressive state. Prostatectomy is another, the result of damage to the parasympathetic nerves embedded in the capsule of the gland. It occurs also in patients who suffer disease of the sacral cord segments and their afferent and efferent connections (e.g., cord tumor, myelitis, tabes, and diabetic and many other polyneuropathies), in which case nocturnal erections are absent. The parasympathetic nerves cannot then be activated to cause tumescence of the corpora cavernosa and corpus spongiosum. The phosphodiesterase inhibitors such as sildenafil (Viagra) have proved to be useful in the treatment of erectile dysfunction in some patients with sexual dysfunction of neurologic cause. During sexual stimulation, it enhances the effect of local nitric oxide on the smooth muscle of the corpus cavernosum; this results in relaxation of the smooth muscle and inflow of blood. The high rate of success of this drug in patients with spinal cord injury indicates that segmental innervation is all that is required for reflexive erection in response to tactile stimulation of the penis.
Diseases of the spinal cord may abolish psychogenic erections but leave reflexive ones intact. In fact, the latter may become overactive, giving rise to sustained painful erections (priapism). This indicates that the segmental mechanism for penile erection is relatively intact. There are many other nonneurologic causes for priapism, among them are sickle cell anemia and other thrombotic states and perineal trauma.
Other sexual difficulties include the premature ejaculation of semen. After lumbar sympathectomy, the semen may be ejected back into the bladder because of paralysis of the periurethral muscle within the prostate, at the verumontanum (colliculus seminalis). Polyneuropathies, such as those caused by diabetes, may be responsible; acute or chronic prostatitis may have a similar effect.
Cerebral disorders of sexual function are discussed further in Chap. 24 (see section on “Altered Sexuality”) and the development of sexual function, in Chap. 27.
NERVOUS SYSTEM CONTROL OF RESPIRATION
Considering that the act of breathing is directed entirely by the nervous system, it is surprising how little attention it has received other than from physiologists. Every component of breathing—the lifelong automatic cycling of inspiration, the transmission of coordinated nerve impulses to and from the respiratory muscles, the translation of systemic influences such as acidosis to the neuromuscular apparatus of the diaphragm—is under neural control. Moreover, respiratory failure is one of the most serious disturbances of neurologic function in comatose states and in neuromuscular diseases such as myasthenia gravis, Guillain-Barré syndrome, amyotrophic lateral sclerosis, muscular dystrophy, and poliomyelitis. Finally, death—or brain death—is now virtually defined in terms of the ability of the nervous system to sustain respiration, a reversion to ancient methods of determining the cessation of all vital forces. Neurologists should be familiar with the alterations of respiration caused by diseases in different parts of the nervous system, the effects of respiratory failure on the brain, and the rationale that underlies modern methods of treatment. A full understanding of respiration requires knowledge of the mechanical and physiologic workings of the lungs as organs of gas exchange; but here we limit our remarks to the nervous system control of breathing.
The Central Respiratory Motor Mechanisms
It has been known for more than a century that breathing is controlled mainly by the lower brainstem, and that each half of the brainstem is capable of producing an independent respiratory rhythm. In patients with poliomyelitis, for example, the occurrence of respiratory failure was associated with lesions in the ventrolateral tegmentum of the medulla (Feldman; Cohen). Until fairly recently, thinking on this subject was dominated by Lumsden’s scheme of the breathing patterns that resulted from sectioning the brainstem of cats at various levels. He postulated the existence of several centers in the pontine tegmentum, each corresponding to an abnormal breathing pattern—a pneumotaxic center, an apneustic center, and a medullary gasping center. This scheme proves to be oversimplified when viewed in the light of modern physiologic findings. Instead, neurons in several discrete regions discharge with each breath and, together, generate the respiratory rhythm. In other words, these sites do not function in isolation, as individual oscillators, but interact with one another to generate the perpetual respiratory cycle and they each contain both inspiratory and expiratory components.
Three paired groups of respiratory nuclei are oriented more or less in columns in the pontine and medullary tegmentum (Fig. 25-8). They comprise (1) a ventral respiratory group (referred to as VRG), extending from the lower to the upper ventral medulla, in the region of the nucleus retroambiguus; (2) a dorsal medullary respiratory group (DRG), located dorsal to the obex and immediately ventromedial to the NTS; and (3) two clusters of cells in the dorsolateral pons in the region of the parabrachial nucleus. From electrical-stimulation experiments, it appears that paired neurons in the dorsal pons may act as “on–off” switches in the transition between inspiration and expiration.
The location of the main centers of respiratory control in the brainstem as currently envisioned from animal experiments and limited human pathology. There are three paired groups of nuclei: (1) The dorsal respiratory group (DRG), containing mainly inspiratory neurons, located in a subnucleus of the nucleus of the tractus solitarius; (2) a ventral respiratory group (VRG), situated near the nucleus ambiguus and containing in its caudal part neurons that fire predominantly during expiration and in its rostral part neurons that are synchronous with inspiration—the latter structure merges rostrally with the Botzinger complex, which is located just behind the facial nucleus and contains neurons that are active mostly during expiration; and (3) a pontine pair of nuclei (PRG), one of which fires in the transition between inspiration and expiration and the other between expiration and inspiration. The intrinsic rhythmicity of the entire system probably depends on interactions between all these regions, but the “pre-Botzinger” area in the rostral ventromedial medulla may play a special role in generating the respiratory rhythm. (Adapted by permission from Duffin et al.)
Inspiratory neurons are concentrated in the dorsal respiratory group and in the rostral portions of the ventral group, some of which have monosynaptic connections to the motor neurons of the phrenic nerves and the nerves to the intercostal muscles. Normal breathing is actively inspiratory and only passively expiratory; however, under some circumstances of increased respiratory drive, the internal intercostal muscles and abdominal muscles actively expel air. The expiratory neurons that mediate this activity are concentrated in the caudal portions of the ventral respiratory group and in the most rostral parts of the dorsal group. On the basis of both neuroanatomic tracer and physiologic studies, it has been determined that these expiratory neurons project to spinal motor neurons and have an inhibitory influence on inspiratory neurons.
The pathway of descending fibers that arises in the inspiratory neurons and terminates on phrenic nerve motor neurons lies just lateral to the anterior horns of the upper cervical cord segments. When these tracts are damaged, automatic but not voluntary diaphragmatic movement is lost. As noted later, the fibers carrying voluntary motor impulses to the diaphragm course more dorsally in the cord. The phrenic motor neurons form a thin column in the medial parts of the ventral horns, extending from the third through fifth cervical cord segments. Damage to these neurons, of course, precludes both voluntary and automatic breathing.
As mentioned, the exact locus from which the breathing rhythm is generated, if there is such a site, is not known. The conventional understanding has been that the DRG was the dominant generator of the respiratory rhythm but the situation is certainly more complex. Animal experiments have focused attention instead on the rostral ventrolateral medulla (VRG). This region contains a group of neurons in the vicinity of the “Botzinger complex” (which itself contains neurons that fire mainly during expiration). Cooling of this area or injection with neurotoxins in animals causes the respiratory rhythm to cease (see the review by Duffin et al). It has also been shown that the paired respiratory nuclei in the pons that are thought to act as switches between inspiration and expiration possess a degree of autonomous rhythmicity but their role in engendering cyclic breathing has not been clarified. Some workers are of the opinion that two or more sets of neurons in the VRG create a rhythm by their reciprocal activity or that oscillations arise within even larger networks (see Blessing for details).
There are also centers in the pons that do not generate respiratory rhythms but may, under extreme circumstances, greatly influence them. One pontine group, the “pneumotaxic center,” modulates the response to hypoxia, hypocapnia, and lung inflation. In general, expiratory neurons are located laterally and inspiratory neurons medially in this center, but there is an additional group that lies between them and remains active during the transition between respiratory phases. Also found in the lower pons is a group of neurons that prevent unrestrained activity of the medullary inspiratory neurons (“apneustic center”). In addition to these ambiguities regarding a “center” for the generation of respiratory rhythm, there is the difficulty that the nuclei described earlier are not well defined in humans.
As to the effects of a unilateral brainstem lesion on ventilation, numerous cases of hypoventilation or total loss of automatic ventilation (“Ondine’s curse”—see further on) have been recorded (Bogousslavsky and colleagues). We have observed several such remarkable cases as well, in most instances caused by a large lateral medullary infarction. If the neural oscillators on each side were totally independent, such a syndrome should not be possible. The likely explanation is that a unilateral lesion interrupts the connections between each of the paired groups of nuclei, which normally synchronize the two sides in the generation of rhythmic bursts of excitatory impulses to spinal motor neurons. It is of interest that in a case of a delimited metastasis to the NTS there was no apparent impact on the breathing pattern until a terminal respiratory arrest (Rhodes and Wightman).
Voluntary Control of Breathing
During speech, swallowing, breathholding, or voluntary hyperventilation, the automaticity of the brainstem mechanisms of respiration is arrested in favor of reflexive or of conscious control of diaphragmatic contraction. The observations of Colebatch and coworkers, using PET scanning, indicate that voluntary control of breathing is associated with activity in the motor and premotor cortex. The experiments of Maskill and associates demonstrated that magnetic cortical stimulation of a region near the cranial vertex activates the diaphragm. Although automatic and voluntary breathing utilize the same pools of cervical motor neurons that give rise to the phrenic nerves, the descending cortical pathways for voluntary breathing are distinct from those utilized by automatic brainstem mechanisms as noted earlier. It is not known whether the voluntary signal bypasses the brainstem mechanisms or is possibly integrated there. When both dorsal descending tracts subserving voluntary control are interrupted, as in the “locked-in syndrome,” the independent, automatic respiratory system in the medulla is capable of maintaining an almost perfectly regular breathing rate of 16 per minute with uniform tidal volumes.
These essential facts do not fully depict the rich interactions between the neuronal groups governing respiration and those for laryngeal and glottic activity that come into play during such coordinated acts as swallowing, sneezing, coughing, and speaking. The brainstem regions that hold breathing in abeyance while swallowing occurs are pertinent to aspiration, a common feature of many neurologic diseases, as discussed further on. The drive applied to these systems is damped in processes such as Parkinson disease, causing discoordination between breathing and swallowing, and may contribute to the problem of aspiration, as also discussed further on.
Afferent Respiratory Influences
A number of signals that modulate respiratory drive originate in chemoreceptors located in the carotid artery. These receptors are influenced both by changes in pH and by hypoxia. Chemoreceptor afferents pass along the carotid sinus nerves, which join the glossopharyngeal nerves and terminate in the NTS. Aortic body receptors, which are less important as detectors of hypoxia, send afferent volleys to the medulla through the aortic nerves, which join the vagus nerves. There are also chemoreceptors in the brainstem, but their precise location is uncertain. Their main locus is thought to be in the ventral medulla, but other areas that are responsive to changes in pH have been demonstrated in animals. What is clear is that these regions are sensitive not to the pH of CSF, as had been thought, but to the pH of the extracellular fluid of the medulla.
Numerous stretch receptors within smooth muscle cells of the airways also project via the vagus nerves to the NTS and influence the depth and duration of breathing. Afferent signals from these specialized nerve endings mediate the Hering-Breuer reflex, described in 1868—a shortened inspiration and decreased tidal volume triggered by excessive lung expansion. The Hering-Breuer mechanism seems not to be important at rest, as bilateral vagal section has no effect on the rate or depth of respiration. These aspects of afferent pulmonary modulation of breathing have been reviewed by Berger and colleagues. It is interesting, however, that patients with high spinal transections and inability to breathe can still sense changes in lung volume, attesting to a nonspinal afferent route to the brainstem from lung receptors, probably through the vagus nerves. In addition, there are receptors located between pulmonary epithelial cells that respond to irritants such as histamine and smoke. They have been implicated in the genesis of asthma. There are also “J-type” receptors in the lung interstitium that are activated by substances in the interstitial fluid of the lungs. These are capable of inducing hyperpnea and probably play a role in driving ventilation under conditions such as pulmonary edema.
Both the diaphragm and the accessory muscles of respiration contain conventional spindle receptors, but their role is not clear; all that can be said is that the diaphragm has a paucity of these receptors compared with other skeletal muscles (a property shared with extraocular muscles) and is therefore not subject to spasticity with corticospinal lesions or to the loss of tone in states such as REM sleep, in which gamma motor neuron activity is greatly diminished.
The common respiratory sensations of breathlessness, air hunger, chest tightness, or shortness of breath, all of which are subsumed under the term dyspnea, have defied neurophysiologic interpretation. In animals, Chen and colleagues from Eldridge’s laboratory have demonstrated that neurons in the thalamus and central midbrain tegmentum discharge in a graduated manner as respiratory drive is increased. These neurons are influenced greatly by afferent information from the chest wall, lung, and chemoreceptors and are postulated to be the thalamic representation of sensation from the thorax that is perceived at a cortical level as dyspnea. However, functional imaging studies indicate that various areas of the cerebrum are activated by dyspnea, mainly the insula and limbic regions.
Aberrant Respiratory Patterns
Many of the most interesting respiratory patterns observed in neurologic disease are found in comatose patients, and several of these patterns have been assigned localizing value, some of uncertain validity: central neurogenic hyperventilation, apneusis, and ataxic breathing. These are discussed in relation to the clinical signs of coma (see Chap. 16) and sleep apnea (see Chap. 18). Some of the most bizarre cadences of breathing—those in which unwanted breaths intrude on speech or those characterized by incoordination of laryngeal closure, diaphragmatic movement, or swallowing or by respiratory tics—have occurred in paraneoplastic brainstem encephalitis. Similar incoordinated patterns occur in certain extrapyramidal diseases. Patterns such as episodic tachypnea up to 100 breaths per minute and loss of voluntary control of breathing were, in the past, noteworthy features of postencephalitic parkinsonism.
In Leeuwenhoek’s disease, named for the discoverer of the microscope who described and was afflicted with the problem, there is an almost continuous epigastric pulsation and dyspnea in association with rhythmic bursts of activity in the inspiratory muscles—a respiratory myoclonus akin to palatal myoclonus (Phillips and Eldridge). Two such cases in our clinical material followed influenza-like illnesses and resolved slowly over months. Another patient with similar movements intermittently causing gasping sounds gave us the impression of having a psychogenic disease.
Cheyne-Stokes breathing, the common and well-known waxing and waning type of cyclic ventilation reported by Cheyne in 1818 and later elaborated by Stokes, has for decades been ascribed to a prolongation of circulation time, as in congestive heart failure; but there are data that support a primary neural origin of the disorder, particularly the observation that it occurs most often in patients with deep hemispheral lesions of the cerebral hemispheres or advanced stages of metabolic encephalopathy. The level of consciousness in these circumstances parallels the respiratory pattern. During the apneic period the patient is less responsive. The onset of respiration is heralded by arousal, marked by eye opening and sometimes vocalization. At the peak of the hyperventilation phase, the patient is maximally awake. Consciousness then wanes followed by slowing of the respiratory rate and finally coma to complete a full cycle. The fact that the level of consciousness changes before the respiratory rate is altered implies that Cheyne-Stokes breathing is only one component of a cyclic autonomic brainstem phenomenon. (See Chap. 16 for further comments on the physiologic explanation for this pattern.)
Another striking aberration of ventilation is a loss of automatic respiration during sleep, with preserved voluntary breathing (Ondine’s curse). The term stems from the German myth in which Ondine, a sea nymph, condemns her unfaithful lover to a loss of all movements and functions that do not require conscious will. Patients with this condition are compelled to remain awake lest they stop breathing, and they must have nighttime mechanical ventilation to survive. Presumably the underlying pathology is one that selectively interrupts the ventrolateral descending medullocervical pathways that subserve automatic breathing. The syndrome has been documented mostly in cases of unilateral and bilateral brainstem infarctions, hemorrhage, encephalitis (neoplastic or infectious—for example, due to Listeria), in Leigh syndrome (a destructive process in the lower brainstem of mitochondrial origin), and with traumatic Duret hemorrhages in the lower brainstem. The issue of a loss of automatic ventilation as a result of a unilateral brainstem lesion has been addressed earlier. A state in which there is complete loss of voluntary control of ventilation but preserved automatic monorhythmic breathing has also been described (Munschauer et al). Incomplete variants of this latter phenomenon are regularly observed in cases of brainstem infarction or severe demyelinating disease, and may be a component of the “locked-in state.”
Often neglected is the dyspnea that patients experience with orthostatic hypotension (orthostatic dyspnea). In a questionnaire given to patients in an autonomic laboratory, Gibbons and Freeman (2005) reported that one-third had this symptom. They proposed that some form of mismatch between lung ventilation and perfusion was the cause.
The congenital central hypoventilation syndrome is thought to be an idiopathic version of the loss of automatic ventilation (see Shannon et al, 1976). This rare condition begins in infancy with apneas and sleep disturbances of varying severity or later in childhood with signs of chronic hypoxia leading to pulmonary hypertension. As mentioned in “Sleep Apnea and Excessive Daytime Sleepiness” in Chap. 18, several subtle changes in the arcuate nucleus of the medulla and a depletion of neurons in regions of the respiratory centers have been found in this condition, but further study is necessary.
Neurologic lesions that cause hyperventilation are diverse and widely located throughout the brain, not just in the brainstem. In clinical practice, episodes of hyperventilation are most often seen in anxiety and panic states. The traditional view of “central neurogenic hyperventilation” as a manifestation of a pontine lesion has been brought into question by the observation that it may occur as a sign of primary cerebral lymphoma, in which postmortem examination has failed to show involvement of the brainstem regions controlling respiration (Plum).
Hiccup (singultus) is a poorly understood phenomenon. It does not seem to serve any useful physiologic purpose, existing only as a nuisance, and is typically not associated with any particular disease. It may occur as a component of the lateral medullary syndrome (see Chap. 33) as in 7 of 51 cases studied by Park and colleagues, with masses in the posterior fossa or medulla, and occasionally with generalized elevation of intracranial pressure, brainstem encephalitis, or with metabolic encephalopathies such as uremia. Rarely, singultation may be provoked by medication, one possible offender in our experience being dexamethasone. Because the triggers of hiccup often seem to arise in epigastric organs adjacent to the diaphragm, it is considered to be a gastrointestinal reflex, more than a respiratory one. A physiologic study by Newsom Davis demonstrated that hiccup is the result of powerful contraction of the diaphragm and intercostal muscles, followed immediately by laryngeal closure. This results in little or no net movement of air. He concluded that the projections from the brainstem responsible for hiccup are independent of the pathways that mediate rhythmic breathing.
Within a single burst or run of hiccups, the frequency remains relatively constant, but at any one time it may range anywhere from 15 to 45 per minute. The contractions are most liable to occur during inspiration and they are inhibited by therapeutic elevation of arterial carbon dioxide (CO2) tension. We cannot vouch for the innumerable home-brewed methods that are said to suppress hiccups (breathholding, induced fright, anesthetization, or stimulation of the external ear canal or concha, etc.), but where the neurologist is asked to help in an intractable case (usually in a male), baclofen is sometimes effective. Drugs that act to empty the stomach (e.g., metoclopramide) may work as well.
Disorders of Ventilation Caused by Neuromuscular Disease
Failure of ventilation in the neuromuscular diseases causes one of two symptom complexes: an acute one occurs in patients with rapidly evolving generalized weakness, such as Guillain-Barré syndrome and myasthenia gravis, and the other in patients with subacute or chronic diseases, such as motor neuron disease, myopathies (acid maltase, nemaline), and muscular dystrophy. The review by Polkey and colleagues provides a more extensive list of diseases that cause these problems. Patients in whom respiratory failure evolves in a matter of hours become anxious, tachycardic, and diaphoretic. They may display paradoxical respiration, in which the abdominal wall retracts during inspiration, owing to the failure of the diaphragm to contract, while the intercostal and accessory muscles create a negative intrathoracic pressure. Or, there is respiratory alternans, a pattern of diaphragmatic descent only on alternate breaths (this is more characteristic of airway obstruction). These signs appear in the acutely ill patient when the vital capacity has been reduced to approximately 10 percent of normal, or 500 mL in the average adult.
Patients with chronic but stable weakness of the respiratory muscles, demonstrate signs of CO2 retention, such as daytime somnolence, headache upon awakening, nightmares, and, in extreme cases, papilledema. The accessory muscles of respiration are recruited in an attempt to maximize tidal volume, and there is a tendency for the patient to gulp or assume a rounded “fish mouth” appearance in an effort to inhale additional air. In general, patients with chronic respiratory difficulty tolerate lower tidal volumes without dyspnea than do patients with acute disease, and symptoms in the former may occur only at night, when respiratory drive is diminished and compensatory mechanisms for obtaining additional air are in abeyance.
Treatment of the two conditions differs. The chronic type of respiratory failure may require only nighttime support of ventilation, which can be provided by negative pressure devices such as a cuirass or preferably, by intermittent positive pressure applied by a tight-fitting mask over the nose (bilevel positive airway pressure [BIPAP] or continuous positive airway pressure [CPAP]). These measures may also be used temporarily in acute situations, but in many cases there will be need of a positive-pressure ventilator that provides a constant volume with each breath. This can be effected only through an endotracheal tube.
Typical ventilator settings in cases of acute mechanical respiratory failure, if there is no pneumonia, are for tidal volumes of 6 to 8 mL/kg, depending on the compliance of the lungs and the patient’s comfort, at a ventilator rate between 4 and 12 breaths per minute, adjusted to the degree of respiratory failure. The tidal volume is kept relatively constant so as to prevent atelectasis, and only the rate is changed as the diaphragm becomes weaker or stronger. Decisions regarding the need for these mechanical devices are frequently difficult, particularly as patients with chronic neuromuscular illnesses often become dependent on a ventilator. Further details regarding the management of ventilation in acute neuromuscular weakness are given in the section on Guillain-Barré syndrome in Chap. 43 (see also monograph by Ropper and colleagues).
The presence of oropharyngeal weakness as a result of the underlying neuromuscular disease may leave the patient’s airway unprotected and require endotracheal intubation before mechanical ventilation becomes necessary. It is even difficult to decide when to remove an endotracheal tube in a patient with oropharyngeal weakness. Because the safety of the swallowing mechanism cannot be assessed with the tube in place, one must be prepared to reintubate the patient or to have a surgeon prepared to perform a tracheostomy after extubation, in the event that aspiration occurs.
We frequently encounter patients in whom the earliest feature of neuromuscular disease is subacute respiratory failure; this is manifest as dyspnea and exercise intolerance but without other overt signs of neuromuscular disease. Most such cases prove to be motor neuron disease, but rare instances of myasthenia gravis (especially the type associated with the MUSK autoantibody), acid maltase deficiency, polymyositis, nemaline myopathy, Lambert-Eaton syndrome, or chronic inflammatory demyelinating polyneuropathy may present in this way. The neurologist may be consulted in these cases after other physicians have found no evidence of intrinsic pulmonary disease. The spirometric flow-volume loop in cases of neuromuscular respiratory failure shows low airflow rates with diminished lung volumes that together simulate restrictive lung disease. Among such patients we have also found instances of isolated unilateral or bilateral phrenic nerve paresis that followed abdominal or cardiac surgery or an infectious illness. The least of these is probably a form of brachial neuritis (see Chap. 46 for a discussion of brachial neuritis).
Neuromuscular respiratory failure in critically ill patients
Neurologists increasingly are being called upon to determine if there is an underlying neuromuscular cause for respiratory failure in a critically ill patient. Malnutrition, hypophosphatemia (induced by hyperalimentation), and hypokalemia always need to be kept in mind as causes of muscular weakness. Aside from the acute neuromuscular diseases listed above, Bolton and colleagues have delineated a critical illness polyneuropathy, which accounts for as many as 40 percent of cases of an inability to wean a patient from the ventilation. Most of these patients have had an episode of sepsis or have multiple organ failure (see Chap. 46). The EMG demonstrates widespread denervation with relative sparing of sensory potentials. Less often, a critical illness myopathy occurs in relation to the administration of high-dose corticosteroids (see Chap. 45). This myopathy occurs mainly in patients who are receiving neuromuscular postsynaptic blocking drugs such as pancuronium simultaneously with high-dose steroids but corticosteroids alone have been implicated.
The Neurologic Basis of Swallowing
The act of swallowing, like breathing, continues periodically through waking and sleep, largely without conscious will or awareness. Swallowing occurs at a natural frequency of about once per minute while an individual is idle; it is suppressed during concentration and emotional excitement.
The fundamental role of swallowing is to move food from the mouth to the esophagus and thereby to begin the process of digestion, but it also serves to empty the oral cavity of saliva and prevent its entry into the respiratory tract. Because the oropharynx is a shared conduit for breathing and swallowing, obligatory reflexes exist to ensure that breathing is held in abeyance during swallowing. Because of this relationship and the frequency with which dysphagia and aspiration complicate neurologic disease, the neural mechanisms that underlie swallowing are of considerable importance to the neurologist and are described here. The reader is also referred to other parts of this book for a discussion of derangements of swallowing consequent upon diseases of the lower cranial nerves (see Chap. 44), of muscle (see Chap. 45), and of the neuromuscular junction (see Chap. 46).
Anatomic and Physiologic Considerations
A highly coordinated sequence of muscle contractions is required to move a bolus of food smoothly and safely through the oropharynx. This programmed activity may be elicited voluntarily or by reflex movements that are triggered by sensory impulses from the posterior pharynx. Swallowing normally begins as the tongue, innervated by cranial nerve XII, sweeps food to the posterior oral cavity, and brings the bolus into contact with the posterior wall of the oropharynx. As the food passes the pillars of the fauces, tactile sensation, carried through nerves IX and X, reflexly triggers (1) the contraction of levator and tensor veli palatini muscles, which close the nasopharynx and prevent nasal regurgitation, followed by (2) the upward and forward movement of the arytenoid cartilages toward the epiglottis (observed as an upward displacement of the hyoid and thyroid cartilages), which closes the airway. With these movements, the epiglottis guides the food into the valleculae and into channels formed by the epiglottic folds and the pharyngeal walls. The airway is closed by sequential contractions of the arytenoid–epiglottic folds, and below them, the false cords, and then the true vocal cords, which seal the trachea.
All of these muscular contractions are effected largely by cranial nerve X (vagus). The palatopharyngeal muscles pull the pharynx up over the bolus and the stylopharyngeal muscles draw the sides of the pharynx outward (nerve IX). At the same time, the upward movement of the larynx opens the cricopharyngeal sphincter. A wave of peristalsis then begins in the pharynx, pushing the bolus through the sphincter into the esophagus. These muscles relax as soon as the bolus reaches the esophagus. The entire swallowing ensemble can be elicited by stimulation of the superior laryngeal nerve (this route is used in experimental studies.)
Reflex swallowing requires only medullary functioning and is retained in the vegetative and locked-in states as well as in normal and anencephalic neonates. The integrated sequence of muscle activity for swallowing is organized in a region of brainstem that roughly comprises a swallowing center, located in the region of the NTS, close to the respiratory centers. This juxtaposition ostensibly allows the refined coordination of swallowing with the cycle of breathing. Besides a programmed period of apnea, there is a slight forced exhalation after each swallow that further prevents aspiration. The studies of Jean, Kessler, and others (cited by Blessing), using microinjections of excitatory neurotransmitters, have localized the swallowing center in animals to a region adjacent to the termination of the superior laryngeal nerve. Unlike the generators of respiratory rhythm, the entire reflex apparatus for swallowing may be located in the NTS. There is, however, no direct connection between the NTS and the cranial nerve motor nuclei. Thus it is presumed that control must be exerted through premotor neurons located in adjacent reticular brainstem regions. There have been few comparable anatomic studies of the structures responsible for swallowing in humans. As to the cortical regions that are involved in swallowing, it appears from PET studies that the inferior precentral gyrus and the posterior inferior frontal gyrus are activated, and lesions in these parts of the brain give rise to the most profound cases of dysphagia.
Weakness or incoordination of the swallowing apparatus is manifest as dysphagia and, at times, aspiration. The patient himself is often able to discriminate one of several types of defects: (1) difficulty initiating swallowing, which leaves solids stuck in the oropharynx; (2) nasal regurgitation of liquids; (3) frequent coughing and choking immediately after swallowing and a hoarse, “wet cough” following the ingestion of fluids; or (4) some combination of these. Extrapyramidal diseases, notably Parkinson disease, reduce the frequency of swallowing and cause an incoordination of breathing and swallowing, as noted later.
It is surprising how often the tongue and the muscles that cause palatal elevation appear on direct examination to act normally despite an obvious failure of coordinated swallowing. Similarly, the use of the gag reflex as a neurologic sign is quite limited, being most helpful when there is a medullary lesion or the lower cranial nerves are damaged. In our experience, palatal elevation in response to touching the posterior pharynx only demonstrates that cranial nerves IX and X and the local musculature are not entirely dysfunctional; in other words, the presence of the reflex does not ensure the smooth coordination of the swallowing mechanism and, more importantly, does not obviate aspiration. Difficulties with swallowing may begin subtly and express themselves as weight loss or as a noticeable increase in the time required to eat a meal. Nodding or sideways head movements to assist the propulsion of the bolus, or the need to repeatedly wash food down with water, are other clues to the presence of dysphagia. Often, recurrent minor pneumonias are the only manifestation of intermittent (“silent”) aspiration.
A defect in the initiation of swallowing is usually attributable to weakness of the tongue and may be a feature of myasthenia gravis, motor neuron disease or rarely, inflammatory disease of the muscle; it may be caused by palsies of the 12th cranial nerve (metastases at the base of the skull or meningoradiculitis, carotid dissection), or to a number of other causes. In all these cases there is usually an associated dysarthria with difficulty pronouncing lingual sounds. The second type of dysphagia, associated with nasal regurgitation of liquids, indicates a failure of velopalatine closure and is characteristic of myasthenia gravis, tenth nerve palsy of any cause, or incoordination of swallowing because of bulbar or pseudobulbar palsy. A nasal pattern of speech with air escaping from the nose is a usual accompaniment.
Viewed from a physiologic perspective, the causes of aspiration fall into four main categories: (1) weakness of the pharyngeal musculature because of lesions of the vagus on one or both sides; (2) myopathy (polymyositis, myotonic and oculopharyngeal dystrophies) or neuromuscular disease (amyotrophic lateral sclerosis and myasthenia gravis); (3) a medullary lesion that affects the NTS or the cranial motor nuclei (lateral medullary infarction is the prototype)—but syringomyelia-syringobulbia and, rarely, multiple sclerosis, polio, and brainstem tumors may have the same effects; or (4) less-well-defined mechanisms of slowed or discoordinated swallowing arising from corticospinal disease (pseudobulbar palsy, hemispheral stroke) or from diseases of the basal ganglia (mainly Parkinson disease) that alter the timing of breathing and swallowing and permit the airway to remain open as food passes through the posterior pharynx. In the latter cases, a decreased frequency of swallowing also causes saliva to pool in the mouth (leading to drooling) and adds to the risk of aspiration.
Because of its frequency, the neurologist will encounter stroke in a cerebral hemisphere as a cause of discoordinated swallowing. The problem is most evident during the first few days after a hemispheral stroke on either side of the brain (Meadows). These effects last days or weeks and render the patient subject to pneumonia and fever. In the clinical and fluoroscopic study by Mann and colleagues, half of patients still had manifest abnormalities of swallowing 6 months after their strokes. For this reason, it has become customary for patients to have swallowing evaluations in the days after acute stroke. Some insight into the nature of swallowing dysfunction after stroke is provided by Hamdy and colleagues, who correlated the presence of dysphagia with a lesser degree of motor representation of pharyngeal muscles in the unaffected hemisphere, as assessed by magnetic stimulation of the cortex.
Pain on swallowing occurs under a different set of circumstances, the one of most neurologic interest being glossopharyngeal neuralgia as discussed in Chaps. 7 and 44.
Videofluoroscopy has become a useful tool in determining the presence of aspiration during swallowing and in differentiating the several types of dysphagia. The movement of the bolus by the tongue, the timing of reflex swallowing, and the closure of the pharyngeal and palatal openings are judged directly by observation of a bolus of food mixed with barium or of liquid barium alone. However, authorities in the field, such as Wiles, whose reviews are recommended (see also Hughes and Wiles), warn that unqualified dependence on videofluoroscopy is unwise. They remark that observation of the patient swallowing water and repeated observation of the patient while eating can be equally informative. Having the patient swallow water is a particularly effective test of laryngeal closure; the presence of coughing, wet hoarseness or breathlessness, and the need to swallow small volumes slowly are indicative of a high risk of aspiration.
Based on bedside observations and on videofluoroscopy studies, an experienced therapist can make recommendations regarding the safety of oral feeding, changes in the consistency and texture of the diet, postural adjustments, and the need to insert a tracheostomy or feeding tube.
Vomiting is a complex, sequential act that may be triggered by numerous external, gastrointestinal, and neural stimuli. The main central nervous system structure of interest in eliciting the vomiting reflex is the area postrema, which is located at the base of the fourth ventricle. The neurons within the area postrema are chemosensitive and are activated by circulating toxins, which have direct access to these neurons because of the absence of a blood–brain barrier. Axons from the area postrema project to the nucleus of the solitary tract (NTS), which is also a convergence point of input from the pharynx, larynx, and gastrointestinal tract. The NTS engages groups of neurons in the medulla, which coordinates the sequential elements of vomiting; there is no “vomiting center,” as reviewed by Hornby. In addition to stimulation of the area postrema, vestibular, pharyngeal (gag reflex), and psychic stimuli can induce vomiting.
The final expulsion of gastric contents is effected through a combination of lowering of intrathoracic pressure by inspiration against a closed glottis and an increase in abdominal pressure during abdominal muscle contraction. Retroperistalsis begins in the small intestine and there is relaxation of the lower esophageal and pyloric sphincters; the stomach itself does not contract.
The vagus carries afferent information from the enteric system as well as conducting efferent signals from the NTS to the gastrointestinal structures. The neurons in the area postrema contain D2 dopamine, 5-HT3 serotonin, opioids, substance P, and acetylcholine receptors, as well as the aquaporin channel. This affords an explanation for the emetic properties of dopaminergic agents and the antiemetic activity of dopamine and serotonin antagonists. However, other potent antiemetics such as ondansetron, a 5-HT3 receptor antagonist, have their effect on vagal afferents.
Lesions near the area postrema, including tumors, hemorrhage, infarctions, and demyelination are the usual neurologic causes of vomiting. We have seen, and it has been reported in the literature, that vomiting may have a relation to the periventricular lesions of neuromyelitis optica due the enrichment of aquaporin-4 channels in this area (Iorio and colleagues). The mechanism of vomiting from raised intracranial pressure has not been fully explored but could be the result of transmission of pressure to the dorsal medulla.
This syndrome of obscure cause is associated with abdominal migraine in children (see Chap. 9), and is a prominent component of Riley-Day dysautonomia. It is also well known as a factitious self-induced disorder, for example, in bulimia.
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